Is ECM2 p.Arg644Trp (c.1930C>T) pathogenic?

ECM2 p.Arg644Trp (c.1930C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.2825); Ultra-rare (popmax 0.0752%, afr).

How common is ECM2 p.Arg644Trp (c.1930C>T) in the general population?

ECM2 p.Arg644Trp (c.1930C>T) is ultra-rare (popmax 0.0752%, afr) (gnomAD).

What do computational predictors say about ECM2 p.Arg644Trp (c.1930C>T)?

AlphaMissense predicts likely benign (score 0.2825) — an in-silico prediction, not a clinical call.

ECM2 p.Arg644Trp

c.1930C>T · rs151070730 · VCV2326747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0752%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2825	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.004	GERP -4.5, phastCons 0.33
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	23.2	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 0.0752% African / African-American · 56/74,432 alleles

Filtering AF 0.0594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0538%

Overall 0.0083% 133/1,602,288 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0752%	1,329
East Asian	0.0134%	7,444
Admixed American	0.0102%	9,817
Remaining individualsnot grpmax-eligible	0.00968%	10,326
South Asian	0.00887%	11,270
European (non-Finnish)	0.00427%	23,445
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,228

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.Arg644Trp
Coding: c.1930C>T
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs151070730
Type: single nucleotide variant
Location: chr9:92500728 (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-arg644trp (accessed [today's date]).

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