rs104894136 — CYP17A1 Arg239*

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.