Is ECM1 p.Pro403Arg (c.1208C>G) pathogenic?

ECM1 p.Pro403Arg (c.1208C>G) is classified Uncertain significance in ECM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: ambiguous (0.4427); Ultra-rare (popmax 0.0156%, eas); Associated with Inborn genetic diseases.

What condition is associated with ECM1 p.Pro403Arg (c.1208C>G)?

ECM1 p.Pro403Arg (c.1208C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ECM1 p.Pro403Arg (c.1208C>G) in the general population?

ECM1 p.Pro403Arg (c.1208C>G) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ECM1 p.Pro403Arg (c.1208C>G)?

AlphaMissense predicts ambiguous (score 0.4427) — an in-silico prediction, not a clinical call.

ECM1 p.Pro403Arg

c.1208C>G · VCV4246404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4427 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4427	ambiguous
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -7.96	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,254 bp · p 0.14 · regional, not allelic
Overall
CADD	25.5	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 0.0156% East Asian · 7/44,866 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000496% 8/1,613,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,409
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Pro403Arg
Coding: c.1208C>G
MANE Select: NM_004425
Type: single nucleotide variant
Location: chr1:150512476 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 403: 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.Pro403Leu 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-pro403arg (accessed [today's date]).

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