Is ECM1 p.Arg323Cys (c.967C>T) pathogenic?

ECM1 p.Arg323Cys (c.967C>T) is classified Uncertain significance in ECM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-04). AlphaMissense: likely benign (0.3175); Ultra-rare (popmax 0.0169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ECM1 p.Arg323Cys (c.967C>T)?

ECM1 p.Arg323Cys (c.967C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ECM1 p.Arg323Cys (c.967C>T) in the general population?

ECM1 p.Arg323Cys (c.967C>T) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about ECM1 p.Arg323Cys (c.967C>T)?

AlphaMissense predicts likely benign (score 0.3175) — an in-silico prediction, not a clinical call.

ECM1 p.Arg323Cys

c.967C>T · rs148594423 · VCV3086984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3175 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3175	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 0.62, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,254 bp · p 0.14 · regional, not allelic
Overall
CADD	24.8	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 0.0169% European (non-Finnish) · 200/1,180,016 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0137% 221/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,900
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.0117%	8,574
East Asian	0.00223%	44,860
South Asian	0.0022%	45,541

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: ECM1
Protein: p.Arg323Cys
Coding: c.967C>T
MANE Select: NM_004425
dbSNP: rs148594423
Type: single nucleotide variant
Location: chr1:150511715 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 323: the '2 x approximate repeats' region

Full ECM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ECM1 p.Arg323His Uncertain significance ★ ⚠ same residue
ECM1 p.Arg185His Uncertain significance ★★ ⚠ same condition
ECM1 p.Asn324His Uncertain significance ★★ ⚠ same condition
ECM1 p.Gln332Arg Uncertain significance ★★ ⚠ same condition
ECM1 p.Phe345Ile Uncertain significance ★★ ⚠ same condition
ECM1 p.Pro169Ala Uncertain significance ★★ ⚠ same condition
ECM1 p.Pro78Ser Uncertain significance ★★ ⚠ same condition
ECM1 p.Ser54Asn Uncertain significance ★★ ⚠ same condition

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/ecm1-p-arg323cys (accessed [today's date]).

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