rs104894136 — CYP17A1 Arg239*

Pathogenic nonsense variant in CYP17A1 introducing a premature stop codon at position 239 (c.715C>T); homozygotes or compound heterozygotes develop complete 17α-hydroxylase/17,20-lyase deficiency with hypertension, hypokalemia, absent pubertal development, and adrenal crisis risk.

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CYP17A1 Arg239* — When Steroidogenesis Hits an Early Stop

A single molecular accident — a C-to-T transition in exon 4 of CYP17A1 — replaces arginine at position 239 with a premature stop codon. The resulting truncated protein retains only the first 238 of 508 amino acid residues, lacking both the substrate-binding pocket and the heme coordination site that give CYP17A111 CYP17A1
Cytochrome P450 17α-hydroxylase/17,20-lyase, a bifunctional enzyme encoded on chromosome 10q24.32 that catalyzes two sequential reactions required for cortisol and sex steroid biosynthesis its catalytic power. The protein is non-functional before it is even folded. The result is the most complete form of 17α-hydroxylase/17,20-lyase deficiency (17OHD)22 17α-hydroxylase/17,20-lyase deficiency (17OHD)
A rare form of congenital adrenal hyperplasia accounting for approximately 1% of all CAH cases, caused by biallelic loss-of-function variants in CYP17A1.

The Mechanism

CYP17A1 sits at the branch point of steroidogenesis in both the adrenal cortex and the gonads. Its first reaction, 17α-hydroxylation33 17α-hydroxylation
Addition of a hydroxyl group to the 17-position of pregnenolone and progesterone, generating the precursors required for cortisol synthesis, converts pregnenolone to 17α-hydroxypregnenolone and progesterone to 17α-hydroxyprogesterone. Its second reaction, 17,20-lyase activity44 17,20-lyase activity
Cleavage of the C17–C20 bond to produce DHEA and androstenedione, the entry point into sex steroid synthesis, is what allows the adrenal gland and gonads to produce sex hormone precursors at all.

Without CYP17A1 function, three simultaneous hormonal disasters unfold. First, cortisol is absent; ACTH rises without feedback restraint, driving bilateral adrenal hyperplasia. Second, the pregnenolone pool that cannot enter the cortisol or sex steroid branches is shunted instead to mineralocorticoids — specifically 11-deoxycorticosterone (DOC) and corticosterone — causing sodium retention, hypertension, and hypokalemia that can persist for years before diagnosis. Third, neither the adrenal gland nor the gonads can synthesize DHEA or androstenedione, so no sex steroids are produced from any source.

The Arg239* truncation is classified as Pathogenic with multiple-submitter concordance in ClinVar55 classified as Pathogenic with multiple-submitter concordance in ClinVar
ClinVar VCV000001782.18, reviewed by GeneDx, Baylor Genetics, and Labcorp Genetics/Invitae with no conflicts. OMIM documents it as allelic variant 609300.0006.

The Evidence

The c.715C>T (Arg239*) variant was identified as the causative mutation in a 2018 case report of a 46,XY adolescent with 17OHD66 2018 case report of a 46,XY adolescent with 17OHD
Zhang et al. 2018, Gynecological Endocrinology, PMID 29345162. The patient developed a rare complication — an adrenal crisis on the first postoperative day after gonadectomy — attributed to insufficient glucocorticoid coverage during surgery, underscoring that 17OHD confers genuine cortisol insufficiency despite the compensatory high corticosterone.

Population-level evidence comes from Willemsen et al. 202577 Willemsen et al. 2025
Meta-analysis of 465 patients across 178 studies, J Clin Endocrinol Metab, PMID 39500362. Across this global cohort, hypertension was present in 57% of patients, hypokalemia in 45%, and primary amenorrhea in 38% of females. Male patients (46,XY) were typically diagnosed earlier because genital dysplasia is apparent at birth or infancy; females were diagnosed later through investigation of amenorrhea and hypertension. Complete loss-of-function variants — including nonsense mutations like Arg239* — were associated with the most severe phenotypes: complete hypocortisolism and absent sexual development.

A literature review of 198 reported 46,XY 17OHD cases88 literature review of 198 reported 46,XY 17OHD cases
Kawashima et al. 2025, Endocrine Journal, PMID 40545346 found that 7% of patients with typical female external genitalia developed spontaneous breast tissue, likely from peripheral aromatization of elevated corticosterone. This clinical variability creates diagnostic challenges: 17OHD can be misidentified as complete androgen insensitivity syndrome or primary ovarian insufficiency without genetic testing.

The variant is absent from gnomAD population databases (all ancestries), consistent with strong negative selection against complete CYP17A1 loss-of-function. TOPMed estimates an allele frequency of approximately 1 in 100,000 chromosomes.

Practical Actions

For heterozygous carriers, no hormonal dysfunction occurs — a single functional copy of CYP17A1 provides sufficient enzyme activity. The clinically meaningful action is reproductive genetic counseling: if both partners carry any CYP17A1 loss-of-function variant, each pregnancy has a 25% chance of producing an affected child with complete 17OHD.

For homozygous or compound heterozygous individuals, management follows a two-pronged approach established across multiple case series. First, glucocorticoid replacement — typically hydrocortisone — suppresses ACTH, halts DOC accumulation, and thereby resolves the mineralocorticoid-mediated hypertension and hypokalemia. The hypertension of 17OHD is not essential hypertension; it is driven by DOC excess and resolves when ACTH is adequately suppressed. Starting antihypertensive therapy without glucocorticoid replacement addresses the symptom but not the cause.

Second, sex hormone replacement is added to establish and maintain secondary sexual development appropriate to the individual's gender identity. In 46,XX individuals: estrogen followed by combined estrogen-progestogen replacement. In 46,XY individuals with female phenotype: estrogen replacement after gonadectomy (gonads are typically dysgenetic or undescended and carry a small malignancy risk), with careful perioperative glucocorticoid stress dosing to prevent adrenal crisis.

Interactions

The Arg239* allele most commonly causes disease in the compound heterozygous state paired with a second CYP17A1 pathogenic variant on the other chromosome. Documented partners include Asian founder variants p.H373L, p.W406R, and p.Y329Kfs, as well as other exon 4–6 mutations. Because the Arg239* variant truncates the protein at codon 239 and eliminates all catalytic function, compound heterozygosity with any other loss-of-function allele produces the same complete-deficiency phenotype as homozygosity.

Related variants in the same gene that are tracked in published case series include the nearby missense p.Arg239Gln (rs2439628), which causes incomplete enzyme impairment and a milder phenotype, and the Ser106Pro variant (rs104894135), another complete loss-of-function allele documented in Chinese and Middle Eastern populations.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

Common genotype — no CYP17A1 Arg239* variant detected

You have two copies of the common reference allele at rs104894136. This is the genotype present in the vast majority of people globally — the A alternate allele causing the Arg239* premature stop codon is absent from population databases and occurs at a frequency of roughly 1 in 100,000 chromosomes at most. Your CYP17A1 steroidogenesis enzyme is not affected by this variant.

AG Heterozygous Carrier Carrier

One copy of the Arg239* variant — carrier of a pathogenic CYP17A1 stop-gain mutation

The Arg239* mutation produces a severely truncated protein of only 238 residues — less than half the normal 508-amino-acid enzyme. This truncated protein cannot fold correctly and has no catalytic activity. In the heterozygous state, the second allele carries a normal CYP17A1 gene that produces sufficient functional enzyme for normal steroidogenesis. Autosomal recessive inheritance means one functional copy is enough to prevent disease.

Studies of compound heterozygous relatives of 17OHD patients suggest carriers have biochemically normal adrenal steroid profiles under resting conditions. Unlike heterozygous carriers of some CYP17A1 missense variants, stop-gain carriers are not expected to show detectable reductions in 17α-hydroxylase activity on ACTH stimulation.

This variant is absent from gnomAD population databases (all ancestries) and has a TOPMed frequency of approximately 1 in 100,000 chromosomes. It is identified almost exclusively through clinical sequencing following the diagnosis of an affected family member.

AA Homozygous — Complete 17α-Hydroxylase Deficiency Homozygous

Two copies of Arg239* — complete loss of CYP17A1 function, causing 17α-hydroxylase/17,20-lyase deficiency

The Arg239* truncation eliminates the C-terminal half of CYP17A1, including the substrate-binding pocket and heme coordination residues essential for both enzymatic activities. With no functional enzyme in the adrenal cortex or gonads, three simultaneous hormonal crises develop:

  1. Cortisol deficiency: ACTH rises without feedback restraint, causing bilateral adrenal hyperplasia. Cortisol is absent, creating genuine adrenal insufficiency with risk of acute adrenal crisis during physiological stress (illness, surgery, trauma). A 46,XY patient with the c.715C>T mutation developed adrenal crisis post-gonadectomy due to inadequate perioperative glucocorticoid coverage (Zhang et al. 2018, PMID 29345162) — the first such reported case in 17OHD.

  2. Mineralocorticoid excess: Steroidogenesis is shunted to 11-deoxycorticosterone (DOC) and corticosterone — potent mineralocorticoids that drive sodium retention, volume expansion, hypertension, and hypokalemia. This hypertension is DOC-mediated, not essential hypertension; it resolves with adequate glucocorticoid replacement.

  3. Sex steroid deficiency: Both 17α-hydroxylase and 17,20-lyase activities are lost. DHEA, androstenedione, and their downstream products cannot be synthesized from any endogenous source. In 46,XX individuals: primary amenorrhea, absent breast development, absent axillary and pubic hair. In 46,XY individuals: external female or ambiguous genitalia (depending on degree of residual enzyme activity, absent here), cryptorchidism or undescended testes, and primary amenorrhea.

Willemsen et al. 2025 (PMID 39500362), the largest systematic review of 17OHD (465 patients, 178 studies), confirmed that complete loss-of-function variants produce the most severe phenotype: all cardinal features present, with hypocortisolism and complete absence of sex hormone production.

The diagnosis is frequently delayed. In 46,XX individuals, it is often only suspected during investigation of primary amenorrhea in the teenage years or early adulthood. In 46,XY individuals with a female phenotype, it can be misidentified as complete androgen insensitivity syndrome. A careful steroid hormone profile — elevated DOC and corticosterone, absent 17α-hydroxyprogesterone and DHEA, elevated ACTH — is the biochemical signature.