Is HTRA3 p.Val89Met (c.265G>A) pathogenic?

HTRA3 p.Val89Met (c.265G>A) is classified Uncertain significance in HTRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: ambiguous (0.4477); Very rare (popmax 0.00194%, amr).

How common is HTRA3 p.Val89Met (c.265G>A) in the general population?

HTRA3 p.Val89Met (c.265G>A) is very rare (popmax 0.00194%, amr) (gnomAD).

What do computational predictors say about HTRA3 p.Val89Met (c.265G>A)?

AlphaMissense predicts ambiguous (score 0.4477) — an in-silico prediction, not a clinical call.

HTRA3 p.Val89Met

c.265G>A · VCV4036865

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4477 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00194%, amr)

Computational evidence

Protein change
AlphaMissense	0.4477	ambiguous
REVEL	0.34	indeterminate
SaProt	LLR -12.45	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 0.98, phastCons 1
Overall
CADD	31.0	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 0.00194% Admixed American · 1/51,538 alleles

Overall 7.24e-05% 1/1,381,094 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: HTRA3
Protein: p.Val89Met
Coding: c.265G>A
MANE Select: NM_004055 · reported on NM_053044
Type: single nucleotide variant
Location: chr4:8270233 (GRCh38)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 89: the calpain catalytic domain; an α-helix

Full HTRA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN5 p.Ser89Pro Uncertain significance ★ ⚠ same residue
CAPN5 p.Arg243Leu Pathogenic ★★ ⚠ same type
CAPN5 p.Arg289Trp Pathogenic ★★ ⚠ same type
CAPN5 p.Ala118Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala183Ser Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala185Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala237Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala245Val 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/htra3-p-val89met (accessed [today's date]).

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