Is HTRA2 p.Phe331Val (c.991T>G) pathogenic?

HTRA2 p.Phe331Val (c.991T>G) is classified Uncertain significance in HTRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.9963); Absent from gnomAD v4.1.

How common is HTRA2 p.Phe331Val (c.991T>G) in the general population?

HTRA2 p.Phe331Val (c.991T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HTRA2 p.Phe331Val (c.991T>G)?

AlphaMissense predicts likely pathogenic (score 0.9963) — an in-silico prediction, not a clinical call.

HTRA2 p.Phe331Val

c.991T>G · rs2529893525 · VCV2651076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9963	likely pathogenic · top 6% in HTRA2
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -13.57	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 7.9	GERP 0.42, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 1,210 bp · p 8.6e-17 · regional, not allelic
Overall
CADD	29.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HTRA2
Protein: p.Phe331Val
Coding: c.991T>G
MANE Select: NM_013247
dbSNP: rs2529893525
Type: single nucleotide variant
Location: chr2:74531648 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.83 · 13 PDB
Residue 331: a β-strand; the 'serine protease' region

Full HTRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTRA2 p.Arg380Ter Pathogenic ★★ same type
HTRA2 p.Gln82Ter Pathogenic ★★ same type
AUP1 p.Pro9Ser Uncertain significance ★★ ⚠ same type
HTRA2 c.507-10T>A Uncertain significance ★★ same type
HTRA2 c.507-9C>A Uncertain significance ★★ same type
HTRA2 p.Ala110Gly Uncertain significance ★★ ⚠ same type
HTRA2 p.Ala415Thr Uncertain significance ★★ ⚠ same type
HTRA2 p.Arg252Gln 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/htra2-p-phe331val (accessed [today's date]).

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