Is ECM1 p.Phe345Ile (c.1033T>A) pathogenic?

ECM1 p.Phe345Ile (c.1033T>A) is classified Uncertain significance in ECM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.589); Ultra-rare (popmax 0.053%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ECM1 p.Phe345Ile (c.1033T>A)?

ECM1 p.Phe345Ile (c.1033T>A) is associated with Inborn genetic diseases (ClinVar).

How common is ECM1 p.Phe345Ile (c.1033T>A) in the general population?

ECM1 p.Phe345Ile (c.1033T>A) is ultra-rare (popmax 0.053%, nfe) (gnomAD).

What do computational predictors say about ECM1 p.Phe345Ile (c.1033T>A)?

AlphaMissense predicts likely pathogenic (score 0.589) — an in-silico prediction, not a clinical call.

ECM1 p.Phe345Ile

c.1033T>A · rs139967544 · VCV2356320

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.053%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.589	likely pathogenic
REVEL	0.635	indeterminate
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP -1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,254 bp · p 0.14 · regional, not allelic
Overall
CADD	22.3	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 0.053% European (non-Finnish) · 625/1,179,376 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0482%

Overall 0.0408% 658/1,612,712 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.053%	1,887
Remaining individualsnot grpmax-eligible	0.0368%	2,715
African / African-American	0.0107%	9,336
Finnishnot grpmax-eligible	0.00313%	31,961

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.Phe345Ile
Coding: c.1033T>A
MANE Select: NM_004425
dbSNP: rs139967544
Type: single nucleotide variant
Location: chr1:150511781 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 345: 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.Arg185His Uncertain significance ★★ ⚠ same condition
ECM1 p.Asn324His Uncertain significance ★★ ⚠ same condition
ECM1 p.Gln332Arg 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
ECM1 c.223+68T>C Uncertain significance ★ same condition
ECM1 c.386-5T>G Conflicting classifications of pathogenicity ★ 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-phe345ile (accessed [today's date]).

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