Is ECM1 p.Arg476Ter (c.1426C>T) pathogenic?

ECM1 p.Arg476Ter (c.1426C>T) is classified Pathogenic/Likely pathogenic in ECM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-06). Very rare (popmax 0.00441%, nfe); Associated with ECM1-related disorders.

What condition is associated with ECM1 p.Arg476Ter (c.1426C>T)?

ECM1 p.Arg476Ter (c.1426C>T) is associated with ECM1-related disorders (ClinVar).

How common is ECM1 p.Arg476Ter (c.1426C>T) in the general population?

ECM1 p.Arg476Ter (c.1426C>T) is very rare (popmax 0.00441%, nfe) (gnomAD).

ECM1 p.Arg476Ter

c.1426C>T · VCV4881990

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Conditions

ECM1-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.50 · evaluated, not missing
Pangolin	Δ0.24	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1	GERP 0.18, phastCons 0.001
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00441% European (non-Finnish) · 52/1,180,040 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00427% 69/1,614,090 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Finnishnot grpmax-eligible	0.00781%	12,808
European (non-Finnish)grpmax	0.00441%	22,693
East Asian	0.00223%	44,900

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg476Ter
Coding: c.1426C>T
MANE Select: NM_004425
Type: single nucleotide variant
Location: chr1:150513270 (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

Disease context

ECM1-related disorders

Similar variants

ECM1 p.Ser293= Likely pathogenic ★ same condition
ECM1 p.Val10Gly Pathogenic ★ same condition
ECM1 p.Phe167Val Uncertain significance ★ ⚠ same condition
ECM1 p.Cys269= Likely benign same condition
ECM1 p.Pro49Gln Likely benign same condition
ECM1 p.Tyr43= Likely benign same condition
ECM1 p.Arg171fs Pathogenic ★ same condition
ECM1 p.Gln81fs Likely pathogenic ★ 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-arg476ter (accessed [today's date]).

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