Is ECM2 p.Val455Ala (c.1364T>C) pathogenic?

ECM2 p.Val455Ala (c.1364T>C) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: ambiguous (0.3994); Very rare (popmax 0.00339%, nfe).

How common is ECM2 p.Val455Ala (c.1364T>C) in the general population?

ECM2 p.Val455Ala (c.1364T>C) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about ECM2 p.Val455Ala (c.1364T>C)?

AlphaMissense predicts ambiguous (score 0.3994) — an in-silico prediction, not a clinical call.

ECM2 p.Val455Ala

c.1364T>C · VCV3843336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3994	ambiguous
REVEL	0.349	indeterminate
SaProt	LLR -12.79	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.3	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	25.0	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 0.00339% European (non-Finnish) · 40/1,178,686 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00281% 41/1,457,052 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,467
Remaining individualsnot grpmax-eligible	0.0016%	62,354

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: ECM2
Protein: p.Val455Ala
Coding: c.1364T>C
MANE Select: NM_001012267 · reported on NM_001393
Type: single nucleotide variant
Location: chr9:92505633 (GRCh38)

Full ECM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/ecm2-p-val455ala (accessed [today's date]).

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