Is ECM2 p.Leu166Phe (c.496C>T) pathogenic?

ECM2 p.Leu166Phe (c.496C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0381%, afr).

How common is ECM2 p.Leu166Phe (c.496C>T) in the general population?

ECM2 p.Leu166Phe (c.496C>T) is ultra-rare (popmax 0.0381%, afr) (gnomAD).

What do computational predictors say about ECM2 p.Leu166Phe (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

ECM2 p.Leu166Phe

c.496C>T · rs147912487 · VCV3086992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.91	GERP -3.4, phastCons 0.006
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	8.057	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0381% African / African-American · 28/73,538 alleles

Filtering AF 0.027% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0233%

Overall 0.00196% 31/1,585,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0381%	2,626
Admixed American	0.00361%	27,734
Remaining individualsnot grpmax-eligible	0.00163%	61,174

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.Leu166Phe
Coding: c.496C>T
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs147912487
Type: single nucleotide variant
Location: chr9:92515189 (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-leu166phe (accessed [today's date]).

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