Is HTRA3 p.Ala392Val (c.1175C>T) pathogenic?

HTRA3 p.Ala392Val (c.1175C>T) is classified Likely benign in HTRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0624); Ultra-rare (popmax 0.0527%, sas).

How common is HTRA3 p.Ala392Val (c.1175C>T) in the general population?

HTRA3 p.Ala392Val (c.1175C>T) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

What do computational predictors say about HTRA3 p.Ala392Val (c.1175C>T)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

HTRA3 p.Ala392Val

c.1175C>T · VCV4677374

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -2.63	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 -0.027	GERP -1.3
Overall
CADD	2.769	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 0.0527% South Asian · 48/91,066 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.00359% 58/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,897
East Asian	0.00668%	14,963
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00267%	37,518
Admixed American	0.00167%	60,024
European (non-Finnish)	0.00017%	589,964

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.Ala392Val
Coding: c.1175C>T
MANE Select: NM_004055 · reported on NM_053044
Type: single nucleotide variant
Location: chr4:8304258 (GRCh38)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 392: the 'domain iii' region

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

Similar variants

HTRA3 p.Ala392Pro Uncertain significance ★ ⚠ same residue
CAPN5 p.Phe392= Likely benign ★ 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

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-ala392val (accessed [today's date]).

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