HSD17B3

Chr 9AR

hydroxysteroid 17-beta dehydrogenase 3

Also known as: EDH17B3, SDR12C2

NCBI Gene: 3293ENSG00000130948UniProt: P37058OMIM: 605573

This enzyme catalyzes the conversion of androstenedione to testosterone, the key androgen driving male development and function. Mutations cause autosomal recessive male pseudohermaphroditism with gynecomastia due to impaired testosterone synthesis. The gene is highly constrained against loss-of-function variants (pLI near 0), indicating essential function for normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismARLOEUF 1.091 OMIM phenotype
Clinical Summary— HSD17B3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
103 unique Pathogenic / Likely Pathogenic· 67 VUS of 392 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.09LOEUF
pLI 0.000
Z-score 1.28
OE 0.67 (0.43–1.09)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.37Z-score
OE missense 0.92 (0.81–1.05)
155 obs / 168.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.67 (0.43–1.09)
0≤0.351.4
Missense OE0.92 (0.81–1.05)
0≤0.61.4
Synonymous OE0.91
0≤1.21.6
LoF obs/exp: 12 / 17.8Missense obs/exp: 155 / 168.4Syn Z: 0.57
DN
0.86top 5%
GOF
0.6542th %ile
LOF
0.1796th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

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

392 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic38
VUS67
Likely Benign168
Benign40
Conflicting12
65
Pathogenic
38
Likely Pathogenic
67
VUS
168
Likely Benign
40
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
9
35
0
65
Likely Pathogenic
12
20
6
0
38
VUS
4
49
12
2
67
Likely Benign
0
5
96
67
168
Benign
0
1
38
1
40
Conflicting
—12
Total378418770390

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HSD17B3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients.
Gonçalves CI et al.·Int J Mol Sci
2022Review
[Clinical, hormonal and molecular genetic characteristics of patients with 46,XY disorders of sex development associated with variants in the HSD17B3 gene].
Kalinchenko NY et al.·Probl Endokrinol (Mosk)
2024Cohort
Serum steroid metabolite profiling by LC-MS/MS in two phenotypic male patients with HSD17B3 deficiency: Implications for hormonal diagnosis.
Fujisawa Y et al.·J Steroid Biochem Mol Biol
2023Cohort
Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.
Rotroff DM et al.·Clin Pharmacol Ther
2018
Lessons from 17β-HSD3 deficiency: Clinical spectrum and complex molecular basis in Chinese patients.
Zhu H et al.·J Steroid Biochem Mol Biol
2023Cohort
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients