Is HSD17B2 p.Pro320Ala (c.958C>G) pathogenic?

HSD17B2 p.Pro320Ala (c.958C>G) is classified Uncertain significance in HSD17B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.1359); Very rare (popmax 8.47e-05%, nfe).

How common is HSD17B2 p.Pro320Ala (c.958C>G) in the general population?

HSD17B2 p.Pro320Ala (c.958C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HSD17B2 p.Pro320Ala (c.958C>G)?

AlphaMissense predicts likely benign (score 0.1359) — an in-silico prediction, not a clinical call.

HSD17B2 p.Pro320Ala

c.958C>G · VCV4272371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1359 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1359	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 63 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.19e-05% 1/1,614,220 alleles · very rare exomes 1/1,461,860 · genomes 0/152,360 · 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: HSD17B2
Protein: p.Pro320Ala
Coding: c.958C>G
MANE Select: NM_002153
Type: single nucleotide variant
Location: chr16:82098230 (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.Pro320Leu Uncertain significance ★ ⚠ same residue
HSD17B2 p.Ala121Thr Benign ★★ ⚠ same type
HSD17B2 p.Ala331Val Likely 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-pro320ala (accessed [today's date]).

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