Is HSD3B1 p.Ser330Cys (c.989C>G) pathogenic?

HSD3B1 p.Ser330Cys (c.989C>G) is classified Uncertain significance in HSD3B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely benign (0.1765); Ultra-rare (popmax 0.0217%, amr).

How common is HSD3B1 p.Ser330Cys (c.989C>G) in the general population?

HSD3B1 p.Ser330Cys (c.989C>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about HSD3B1 p.Ser330Cys (c.989C>G)?

AlphaMissense predicts likely benign (score 0.1765) — an in-silico prediction, not a clinical call.

HSD3B1 p.Ser330Cys

c.989C>G · VCV4677044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1765 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1765	likely benign
REVEL	0.764	pathogenic-leaning
SaProt	LLR -9.57	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.85, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,165 bp · p 0.096 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/60,012 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000805% 13/1,614,068 alleles · ultra-rare exomes 13/1,461,830 · genomes 0/152,238 · 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: HSD3B1
Protein: p.Ser330Cys
Coding: c.989C>G
MANE Select: NM_000862
Type: single nucleotide variant
Location: chr1:119514512 (GRCh38)
Gene constraint: LOEUF 1.606 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.03

Full HSD3B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSD3B1 p.Ile79Val Benign ★★ same type
HSD3B1 p.Ala168Val Uncertain significance ★ ⚠ same type
HSD3B1 p.Ala246Ser Uncertain significance ★ ⚠ same type
HSD3B1 p.Ala246Val Uncertain significance ★ ⚠ same type
HSD3B1 p.Ala83Thr Uncertain significance ★ ⚠ same type
HSD3B1 p.Arg21Cys Uncertain significance ★ ⚠ same type
HSD3B1 p.Arg21His Uncertain significance ★ ⚠ same type
HSD3B1 p.Arg317Cys Uncertain significance ★ ⚠ same type

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/hsd3b1-p-ser330cys (accessed [today's date]).

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