Is HSD3B2 p.Ser329Phe (c.986C>T) pathogenic?

HSD3B2 p.Ser329Phe (c.986C>T) is classified Uncertain significance in HSD3B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely pathogenic (0.5785); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HSD3B2 p.Ser329Phe (c.986C>T)?

HSD3B2 p.Ser329Phe (c.986C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HSD3B2 p.Ser329Phe (c.986C>T) in the general population?

HSD3B2 p.Ser329Phe (c.986C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about HSD3B2 p.Ser329Phe (c.986C>T)?

AlphaMissense predicts likely pathogenic (score 0.5785) — an in-silico prediction, not a clinical call.

HSD3B2 p.Ser329Phe

c.986C>T · rs749915716 · VCV2254261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5785	likely pathogenic
REVEL	0.633	indeterminate
SaProt	LLR -12.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.87, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,197 bp · p 0.07 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,960 alleles · very rare exomes 0/1,461,806 · genomes 2/152,154 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HSD3B2
Protein: p.Ser329Phe
Coding: c.986C>T
MANE Select: NM_000198
dbSNP: rs749915716
Type: single nucleotide variant
Location: chr1:119422487 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.30

Full HSD3B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HSD3B2 p.Arg278His Uncertain significance ★★ ⚠ same condition
HSD3B2 p.Gly140Ser Uncertain significance ★★ ⚠ same condition
HSD3B2 p.Gly89Val Uncertain significance ★★ ⚠ same condition
HSD3B2 p.Ser301Arg Uncertain significance ★★ ⚠ same condition
HSD3B2 p.Tyr156His Uncertain significance ★★ ⚠ same condition
HSD3B2 p.Arg362Gln Likely benign ★★ same condition
HSD3B2 p.Val101Leu Likely benign ★★ same condition
HSD3B2 p.Ala199Ser Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hsd3b2-p-ser329phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown