Is HSD17B2 p.Pro262Arg (c.785C>G) pathogenic?

HSD17B2 p.Pro262Arg (c.785C>G) is classified Uncertain significance in HSD17B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.8779); Very rare (popmax 8.48e-05%, nfe).

How common is HSD17B2 p.Pro262Arg (c.785C>G) in the general population?

HSD17B2 p.Pro262Arg (c.785C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about HSD17B2 p.Pro262Arg (c.785C>G)?

AlphaMissense predicts likely pathogenic (score 0.8779) — an in-silico prediction, not a clinical call.

HSD17B2 p.Pro262Arg

c.785C>G · VCV4272370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8779	likely pathogenic · top 9% in HSD17B2
REVEL	0.667	pathogenic-leaning
SaProt	LLR -14.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 63 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	26.3	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 8.48e-05% European (non-Finnish) · 1/1,179,844 alleles

Overall 6.84e-05% 1/1,461,644 alleles · very rare

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.Pro262Arg
Coding: c.785C>G
MANE Select: NM_002153
Type: single nucleotide variant
Location: chr16:82091022 (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.Pro262Leu 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-pro262arg (accessed [today's date]).

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