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
83 unique Pathogenic / Likely Pathogenic· 44 VUS of 292 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

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56
Likely Pathogenic27
VUS44
Likely Benign137
Benign15
Conflicting11
56
Pathogenic
27
Likely Pathogenic
44
VUS
137
Likely Benign
15
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
7
31
0
56
Likely Pathogenic
9
14
4
0
27
VUS
3
33
7
1
44
Likely Benign
0
5
77
55
137
Benign
0
1
13
1
15
Conflicting
—11
Total306013257290

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 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Functional Analysis of HSD17B3-Deficient Male Mice Reveals Roles for HSD17B7 and HSD17B12 in Testosterone Biosynthesis.
Lawrence BM et al.·Endocrinology
2025Open AccessFunctional
Dynamics of HSD17B3 expression in human fetal testis: implications for the role of Sertoli cells in fetal testosterone biosynthesis.
Planinic A et al.·Front Cell Dev Biol
2024Open Access
HSD17B1 Compensates for HSD17B3 Deficiency in Fetal Mouse Testis but Not in Adults.
Junnila A et al.·Endocrinology
2024Functional
[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)
2024Open AccessCohort
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
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