Is HSD17B2 p.Ala331Val (c.992C>T) pathogenic?

HSD17B2 p.Ala331Val (c.992C>T) is classified Likely benign in HSD17B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-19). AlphaMissense: ambiguous (0.3843); Rare (popmax 0.405%, afr).

How common is HSD17B2 p.Ala331Val (c.992C>T) in the general population?

HSD17B2 p.Ala331Val (c.992C>T) is rare (popmax 0.405%, afr) (gnomAD).

What do computational predictors say about HSD17B2 p.Ala331Val (c.992C>T)?

AlphaMissense predicts ambiguous (score 0.3843) — an in-silico prediction, not a clinical call.

HSD17B2 p.Ala331Val

c.992C>T · rs142879258 · VCV729817

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3843 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.405%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3843	ambiguous
REVEL	0.231	benign-leaning
SaProt	LLR -11.01	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.30	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 63 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	20.8	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 0.405% African / African-American · 304/75,032 alleles

Filtering AF 0.368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.353%

Overall 0.0211% 341/1,614,174 alleles · rare exomes 164/1,461,862 · genomes 177/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.405%	247
Admixed American	0.0267%	3,752
Remaining individualsnot grpmax-eligible	0.016%	6,251
South Asian	0.0011%	91,088
European (non-Finnish)	0.000847%	118,003

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: HSD17B2
Protein: p.Ala331Val
Coding: c.992C>T
MANE Select: NM_002153
dbSNP: rs142879258
Type: single nucleotide variant
Location: chr16:82098264 (GRCh38)
Gene constraint: LOEUF 1.567 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.62

Full HSD17B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSD17B2 p.Ala331Glu Uncertain significance ★ ⚠ same residue
HSD17B2 p.Ala331Thr Uncertain significance ★ ⚠ same residue
HSD17B2 p.Ala121Thr Benign ★★ ⚠ same type
HSD17B2 p.Met226Val Benign ★★ same type
HSD17B2 p.Thr240Ser Benign ★★ same type
HSD17B2 p.Ala230Thr Uncertain significance ★ same type
HSD17B2 p.Ala270Thr Uncertain significance ★ ⚠ same type
HSD17B2 p.Ala289Ser 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/hsd17b2-p-ala331val (accessed [today's date]).

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