Is ECM1 p.Arg448His (c.1343G>A) pathogenic?

ECM1 p.Arg448His (c.1343G>A) is classified Benign in ECM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0762); Rare (popmax 0.348%, sas).

How common is ECM1 p.Arg448His (c.1343G>A) in the general population?

ECM1 p.Arg448His (c.1343G>A) is rare (popmax 0.348%, sas) (gnomAD).

What do computational predictors say about ECM1 p.Arg448His (c.1343G>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

ECM1 p.Arg448His

c.1343G>A · rs147907925 · VCV737232

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.348%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -4.7
Regional constraint	o/e 0.94	unconstrained · MANE · 5,254 bp · p 0.14 · regional, not allelic
Overall
CADD	10.51	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 0.348% South Asian · 317/91,062 alleles

Filtering AF 0.317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.304%

Overall 0.025% 403/1,614,052 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.348%	287
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0133%	7,499
African / African-American	0.00667%	15,000
European (non-Finnish)	0.00398%	25,107
East Asian	0.00223%	44,880

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.Arg448His
Coding: c.1343G>A
MANE Select: NM_004425
dbSNP: rs147907925
Type: single nucleotide variant
Location: chr1:150512763 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05

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

Similar variants

ECM1 p.Arg254Ter Pathogenic ★★ same type
ECM1 p.Arg416Ter Pathogenic/Likely pathogenic ★★ same type
ECM1 p.Arg476Ter Pathogenic/Likely pathogenic ★★ same type
ECM1 p.Arg53Ter Pathogenic ★★ same type
ECM1 p.Cys269Tyr Pathogenic/Likely pathogenic ★★ same type
ECM1 c.122-3T>G Uncertain significance ★★ same type
ECM1 p.Arg185His Uncertain significance ★★ ⚠ same type
ECM1 p.Asn324His Uncertain significance ★★ ⚠ same type

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-arg448his (accessed [today's date]).

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