Is HTRA3 p.Pro377Leu (c.1130C>T) pathogenic?

HTRA3 p.Pro377Leu (c.1130C>T) is classified Uncertain significance in HTRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1187); Very rare (popmax 0.00668%, eas).

How common is HTRA3 p.Pro377Leu (c.1130C>T) in the general population?

HTRA3 p.Pro377Leu (c.1130C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about HTRA3 p.Pro377Leu (c.1130C>T)?

AlphaMissense predicts likely benign (score 0.1187) — an in-silico prediction, not a clinical call.

HTRA3 p.Pro377Leu

c.1130C>T · VCV3285071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1187	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -11.71	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.6, phastCons 1
Overall
CADD	22.7	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 0.00668% East Asian · 3/44,908 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00217% 35/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,969
European (non-Finnish)	0.00254%	39,334
Admixed American	0.00167%	60,002
South Asian	0.0011%	91,088

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.Pro377Leu
Coding: c.1130C>T
MANE Select: NM_004055 · reported on NM_053044
Type: single nucleotide variant
Location: chr4:8304213 (GRCh38)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 377: the 'domain iii' region

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

Similar variants

HTRA3 p.Pro377Arg Uncertain significance ★ ⚠ same residue
CAPN5 p.Cys377= 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-pro377leu (accessed [today's date]).

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