Is HTRA3 p.Pro35Arg (c.104C>G) pathogenic?

HTRA3 p.Pro35Arg (c.104C>G) is classified Uncertain significance in HTRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.1589); Ultra-rare (popmax 0.0388%, afr).

How common is HTRA3 p.Pro35Arg (c.104C>G) in the general population?

HTRA3 p.Pro35Arg (c.104C>G) is ultra-rare (popmax 0.0388%, afr) (gnomAD).

What do computational predictors say about HTRA3 p.Pro35Arg (c.104C>G)?

AlphaMissense predicts likely benign (score 0.1589) — an in-silico prediction, not a clinical call.

HTRA3 p.Pro35Arg

c.104C>G · rs528115462 · VCV2546256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1589	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -8.46	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 2.9	GERP 1.7, phastCons 0.99
Overall
CADD	25.4	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 0.0388% African / African-American · 27/69,668 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.00178% 27/1,516,086 alleles · ultra-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.Pro35Arg
Coding: c.104C>G
MANE Select: NM_004055 · reported on NM_053044
dbSNP: rs528115462
Type: single nucleotide variant
Location: chr4:8270072 (GRCh38)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 35: the calpain catalytic domain

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

Similar variants

CAPN5 p.Thr35Ala Uncertain significance ★ ⚠ same residue
CAPN5 p.Thr35Ile Uncertain significance ★ ⚠ same residue
OMP p.Arg35Cys Uncertain significance ★ ⚠ same residue
CAPN5 p.Thr35fs 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

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-pro35arg (accessed [today's date]).

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