Is ECM2 p.Pro480Leu (c.1439C>T) pathogenic?

ECM2 p.Pro480Leu (c.1439C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely pathogenic (0.67); Very rare (popmax 0.00224%, eas).

How common is ECM2 p.Pro480Leu (c.1439C>T) in the general population?

ECM2 p.Pro480Leu (c.1439C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ECM2 p.Pro480Leu (c.1439C>T)?

AlphaMissense predicts likely pathogenic (score 0.67) — an in-silico prediction, not a clinical call.

ECM2 p.Pro480Leu

c.1439C>T · rs769232573 · VCV2481767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.67 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.67	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -10.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00224% East Asian · 1/44,722 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000276% 4/1,450,754 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,722
South Asian	0.00114%	87,554
European (non-Finnish)	0.00017%	588,647

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.Pro480Leu
Coding: c.1439C>T
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs769232573
Type: single nucleotide variant
Location: chr9:92505558 (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-pro480leu (accessed [today's date]).

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