AKR1C4
Chr 10ARaldo-keto reductase family 1 member C4
Also known as: 3-alpha-HSD, C11, CDR, CHDR, DD-4, DD4, HAKRA
The AKR1C4 protein is a cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids and is required for male sex determination as a component of the "backdoor" androgen biosynthesis pathway that generates 5α-dihydrotestosterone. Mutations cause autosomal recessive 46,XY sex reversal 8, where it acts as a modifier gene affecting male sexual development. The gene shows high tolerance to loss-of-function variants (LOEUF 1.719), suggesting that complete loss of function may be required for disease manifestation.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
The highest-scoring mechanism for this gene is dominant-negative.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
150 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 24 | 0 | 24 |
Likely Pathogenic | 0 | 0 | 2 | 0 | 2 |
VUS | 1 | 54 | 18 | 1 | 74 |
Likely Benign | 0 | 7 | 17 | 14 | 38 |
Benign | 0 | 5 | 3 | 1 | 9 |
| Total | 1 | 66 | 64 | 16 | 147 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
AKR1C4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools