Is ECM1 p.Arg385His (c.1154G>A) pathogenic?

ECM1 p.Arg385His (c.1154G>A) is classified Benign in ECM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0583); Low-frequency (popmax 3.78%, sas).

How common is ECM1 p.Arg385His (c.1154G>A) in the general population?

ECM1 p.Arg385His (c.1154G>A) is low-frequency (popmax 3.78%, sas) (gnomAD).

What do computational predictors say about ECM1 p.Arg385His (c.1154G>A)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

ECM1 p.Arg385His

c.1154G>A · rs375957458 · VCV711736

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.78%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0583	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -6.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.043	GERP -2.9
Regional constraint	o/e 0.94	unconstrained · MANE · 5,254 bp · p 0.14 · regional, not allelic
Overall
CADD	0.6	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 3.78% South Asian · 3,437/91,008 alleles

Filtering AF 3.67% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.63%

Overall 0.226% 3,645/1,613,326 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	3.78%	26
Remaining individualsnot grpmax-eligible	0.232%	431
Middle Eastern	0.181%	551
African / African-American	0.0147%	6,794
East Asian	0.00892%	11,210
European (non-Finnish)	0.00305%	32,775
Admixed American	0.00167%	59,876

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.Arg385His
Coding: c.1154G>A
MANE Select: NM_004425
dbSNP: rs375957458
Type: single nucleotide variant
Location: chr1:150512422 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 385: the '2 x approximate repeats' region

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-arg385his (accessed [today's date]).

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