Is HTRA3 p.Ala10Pro (c.28G>C) pathogenic?

HTRA3 p.Ala10Pro (c.28G>C) is classified Uncertain significance in HTRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely benign (0.1713); Absent from gnomAD v4.1.

How common is HTRA3 p.Ala10Pro (c.28G>C) in the general population?

HTRA3 p.Ala10Pro (c.28G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HTRA3 p.Ala10Pro (c.28G>C)?

AlphaMissense predicts likely benign (score 0.1713) — an in-silico prediction, not a clinical call.

HTRA3 p.Ala10Pro

c.28G>C · VCV3285072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1713 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1713	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -9.88	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 0.23	GERP -3.1
Overall
CADD	14.51	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

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: HTRA3
Protein: p.Ala10Pro
Coding: c.28G>C
MANE Select: NM_004055 · reported on NM_053044
Type: single nucleotide variant
Location: chr4:8269996 (GRCh38)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 10: an α-helix

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

Similar variants

CAPN5 p.Asp10Glu Benign/Likely benign ★★ same residue
CAPN5 p.Asp10Asn Uncertain significance ★ ⚠ same residue
CAPN5 p.Asp10Gly Uncertain significance ★ ⚠ same residue
CAPN5 p.Asp10Tyr Uncertain significance ★ ⚠ same residue
CAPN5 p.Asp10= Likely benign ★ same residue
CAPN5 p.Arg243Leu Pathogenic ★★ same type
CAPN5 p.Arg289Trp Pathogenic ★★ ⚠ same type
CAPN5 p.Ala118Val 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-ala10pro (accessed [today's date]).

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