Is ECM2 p.Arg266Cys (c.796C>T) pathogenic?

ECM2 p.Arg266Cys (c.796C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1075); Ultra-rare (popmax 0.0668%, afr).

How common is ECM2 p.Arg266Cys (c.796C>T) in the general population?

ECM2 p.Arg266Cys (c.796C>T) is ultra-rare (popmax 0.0668%, afr) (gnomAD).

What do computational predictors say about ECM2 p.Arg266Cys (c.796C>T)?

AlphaMissense predicts likely benign (score 0.1075) — an in-silico prediction, not a clinical call.

ECM2 p.Arg266Cys

c.796C>T · rs142591312 · VCV3086997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1075	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -12.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.1	GERP -3.8
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	12.04	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 0.0668% African / African-American · 50/74,802 alleles

Filtering AF 0.0521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0468%

Overall 0.00434% 70/1,613,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0668%	1,496
Remaining individualsnot grpmax-eligible	0.0064%	15,616
South Asian	0.0055%	18,196
Admixed American	0.005%	19,985
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
European (non-Finnish)	0.000593%	168,519

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.Arg266Cys
Coding: c.796C>T
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs142591312
Type: single nucleotide variant
Location: chr9:92514889 (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-arg266cys (accessed [today's date]).

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