Is ECM2 p.Leu466Pro (c.1397T>C) pathogenic?

ECM2 p.Leu466Pro (c.1397T>C) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.956); Very rare (popmax 8.48e-05%, nfe).

How common is ECM2 p.Leu466Pro (c.1397T>C) in the general population?

ECM2 p.Leu466Pro (c.1397T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ECM2 p.Leu466Pro (c.1397T>C)?

AlphaMissense predicts likely pathogenic (score 0.956) — an in-silico prediction, not a clinical call.

ECM2 p.Leu466Pro

c.1397T>C · rs2492037712 · VCV2281663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.956	likely pathogenic
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -17.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	28.5	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 8.48e-05% European (non-Finnish) · 1/1,179,344 alleles

Overall 6.85e-05% 1/1,459,320 alleles · very 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: ECM2
Protein: p.Leu466Pro
Coding: c.1397T>C
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs2492037712
Type: single nucleotide variant
Location: chr9:92505600 (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-leu466pro (accessed [today's date]).

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