rs104894143 — CYP17A1 W406R (Trp406Arg)

Pathogenic missense variant in CYP17A1 causing complete loss of 17α-hydroxylase/17,20-lyase activity; homozygotes develop 17α-hydroxylase deficiency (CAH) with absent sex steroids, primary amenorrhea, and mineralocorticoid excess

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CYP17A1 W406R — The Steroid Synthesis Null Allele

CYP17A1 encodes 17α-hydroxylase/17,20-lyase11 17α-hydroxylase/17,20-lyase
a dual-function cytochrome P450 enzyme that sits at a critical branch point in adrenal and gonadal steroid synthesis. Without this enzyme, the steroid pathway cannot produce cortisol, sex hormones (androgens and estrogens), or DHEA. Instead, precursors accumulate upstream — particularly mineralocorticoids22 mineralocorticoids
aldosterone-pathway steroids that regulate blood pressure and electrolytes, including deoxycorticosterone (DOC), which causes the mineralocorticoid excess syndrome characteristic of the disease.

The W406R variant (c.1216T>C in coding-strand notation; A>G on the GRCh38 plus strand at chr10:102,831,535) substitutes a tryptophan for arginine at position 406. This single amino acid change completely abolishes both catalytic activities of the enzyme. rs104894143 is the most prevalent pathogenic CYP17A1 allele identified in Brazilian and Spanish-ancestry populations, accounting for approximately 50% of mutant alleles in the largest case series to date.

The Mechanism

CYP17A1 catalyzes two sequential reactions. The first (17α-hydroxylation33 17α-hydroxylation
converts pregnenolone → 17-hydroxypregnenolone and progesterone → 17-hydroxyprogesterone) is required for cortisol synthesis in the adrenal cortex. The second (17,20-lyase activity) converts 17-hydroxylated substrates to DHEA and androstenedione — the precursors to all androgens and estrogens in both the gonads and adrenal gland.

Tryptophan 406 lies in the enzyme's active site in a region critical for haem coordination and substrate binding. Replacing it with the bulkier, charged arginine disrupts the active site geometry. In vitro expression studies44 In vitro expression studies
using COS-7 cells and yeast microsomes confirm that W406R produces a completely inactive enzyme — no detectable 17α-hydroxylase or 17,20-lyase activity above background, a finding consistent across multiple independent laboratories.

Carriers of one W406R allele (AG genotype) retain one functional copy of CYP17A1.

The Evidence

The clearest description of the W406R allele's phenotypic consequences comes from Costa-Santos et al. 200455 Costa-Santos et al. 2004
24 patients from 19 Brazilian families, Emory University collaboration, which found that W406R accounts for half of all pathogenic CYP17A1 alleles in their cohort and appears to represent a founder mutation in Spanish-descent populations.

Among homozygous and compound-heterozygous affected individuals studied by Carvalho et al. 201666 Carvalho et al. 2016
n=16 female patients with CYP17A1 mutations, Fertility and Sterility, the clinical picture is consistent: 71% had primary amenorrhea, 88% had hypertension at diagnosis, 62% had ovarian macrocysts, and three patients required surgery for ovarian torsion or rupture. Pubic hair was absent or sparse in all patients. Despite this severe phenotype, the same study concluded that fertility is achievable through assisted reproductive techniques with appropriate hormonal management.

A 2016 case report77 2016 case report
Bianchi et al., J Clin Endocrinol Metab documented the first successful live birth in a W406R carrier (compound heterozygote W406R/P428L) using a progestin-primed ovarian stimulation protocol, glucocorticoid pre-treatment to suppress the elevated endogenous progesterone below 1 ng/mL, and frozen-thawed embryo transfer. The child was born healthy after delivery at 30 weeks.

Epidemiologically, 17α-hydroxylase deficiency is rare — approximately 1 in 50,000 newborns globally — but considerably more common in populations with Portuguese founder ancestry. The G allele at rs104894143 is absent from gnomAD exomes (>1.4 million alleles) and detectable at only 7 per million alleles in gnomAD genomes, consistent with a severe recessive disease allele under strong purifying selection.

Practical Implications

For heterozygous carriers (AG genotype): Carriers are clinically asymptomatic but carry a 25% risk of having an affected child with another carrier. Genetic counseling and partner testing are appropriate before family planning. Carriers considering IVF have the option of preimplantation genetic testing (PGT) to select unaffected embryos.

For homozygotes (GG genotype): Full 17α-hydroxylase/17,20-lyase deficiency requires lifelong glucocorticoid replacement (to suppress ACTH and mineralocorticoid precursor overproduction) and sex hormone replacement (estrogen/progesterone in 46,XX; testosterone in 46,XY). Blood pressure and electrolytes require monitoring due to mineralocorticoid excess. With modern hormone replacement, fertility is possible for 46,XX women using IVF with glucocorticoid pre-treatment to normalize elevated progesterone before embryo transfer.

Interactions

rs743572 (CYP17A1 promoter -34 T>C): This variant in the same gene affects CYP17A1 expression levels through a regulatory mechanism rather than enzyme structure. Individuals who are AG or GG at rs104894143 and also carry the expression-altering promoter variant may have a modified phenotype, though this compound scenario has not been systematically studied — the rarity of the coding mutation makes compound observations uncommon.

Compound heterozygosity within CYP17A1: The literature documents numerous patients who carry W406R on one chromosome and a different CYP17A1 pathogenic variant on the other (e.g. R362C, P428L, Y329D). These compound heterozygotes phenotypically resemble homozygotes and require the same clinical management. Genetic testing should sequence the full CYP17A1 gene to exclude compound heterozygosity in any carrier of W406R.

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-Carrier Normal

No W406R variant detected — standard CYP17A1 steroid synthesis pathway

You carry two copies of the reference A allele at rs104894143. This means you do not carry the W406R pathogenic variant in CYP17A1. Your 17α-hydroxylase/17,20-lyase enzyme is expected to function normally through this locus. The vast majority of people globally share this genotype — the G allele is detected at fewer than 1 in 100,000 alleles in large population databases.

AG Carrier Carrier

One copy of the W406R pathogenic variant — asymptomatic carrier with subclinical steroid biosynthetic findings

The W406R allele (c.1216T>C on the coding strand; A>G on the genomic plus strand) is one of the most prevalent CYP17A1 pathogenic variants in populations of Portuguese and Spanish ancestry, where it appears to represent a founder mutation. In Brazilian cohorts, it accounts for approximately half of all pathogenic CYP17A1 alleles.

The reproductive genetics implications are the most actionable aspect of carrier status. 17α-hydroxylase deficiency follows autosomal recessive inheritance: two loss-of-function alleles are required for the disease phenotype. Carrier status in a partner planning pregnancies warrants partner genetic testing for CYP17A1 pathogenic variants before conception.

GG Homozygous — 17α-Hydroxylase Deficient Homozygous

Two copies of the W406R pathogenic variant — complete 17α-hydroxylase/17,20-lyase deficiency

Homozygosity for W406R means both copies of CYP17A1 produce a completely inactive enzyme. In vitro expression studies confirm zero residual activity. The metabolic consequence is a complete block at the 17α-hydroxylation step: pregnenolone and progesterone cannot enter the cortisol or sex-steroid pathways and instead accumulate, with overflow into the mineralocorticoid pathway producing large amounts of deoxycorticosterone (DOC) and corticosterone. The result is mineralocorticoid excess (hypertension, hypokalemia, suppressed renin and aldosterone) combined with cortisol and sex-steroid deficiency.

Elevated progesterone is the signature biochemical finding and a practical diagnostic marker — basal progesterone above 1.8 ng/mL has high sensitivity for the diagnosis. All 11 patients in Martin et al. 2003 had elevated basal progesterone (1.8–38 ng/mL).

Ovarian complications in 46,XX women require monitoring: 62% of patients in the largest series had ovarian macrocysts, and surgical intervention for torsion was required in 3 of 16 patients. Appropriate glucocorticoid suppression of excess ACTH (which drives ovarian cyst formation) reduces cyst burden.

Fertility is possible for 46,XX women using IVF: the published protocol involves dexamethasone or low-dose glucocorticoid pre-treatment to suppress elevated endogenous progesterone to below 1 ng/mL before embryo transfer, plus estradiol supplementation for endometrial preparation. The first successful live birth in a W406R carrier was reported in 2016.

This genotype should be managed by a specialist in disorders of sex development or a pediatric/adult endocrinologist with experience in congenital adrenal hyperplasia. Genetic counseling is essential for family planning.