Is ECM1 p.Arg254Ter (c.760C>T) pathogenic?

ECM1 p.Arg254Ter (c.760C>T) is classified Pathogenic in ECM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-03). Very rare (popmax 0.00267%, afr); Associated with lipoid proteinosis.

What condition is associated with ECM1 p.Arg254Ter (c.760C>T)?

ECM1 p.Arg254Ter (c.760C>T) is associated with lipoid proteinosis (ClinVar).

How common is ECM1 p.Arg254Ter (c.760C>T) in the general population?

ECM1 p.Arg254Ter (c.760C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

ECM1 p.Arg254Ter

c.760C>T · rs1560266014 · VCV987237

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

lipoid proteinosis

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	predicted	premature termination codon in exon 7 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.5, phastCons 1
Overall
CADD	38.0	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 0.00267% African / African-American · 2/75,038 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000616% 9/1,461,862 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-Americangrpmax	0.00267%	37,519
European (non-Finnish)	0.000424%	236,003

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.Arg254Ter
Coding: c.760C>T
MANE Select: NM_004425
dbSNP: rs1560266014
Type: single nucleotide variant
Location: chr1:150511508 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 254: the '2 x approximate repeats' region

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

Disease context

lipoid proteinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ECM1 p.Arg416Ter Pathogenic/Likely pathogenic ★★ same condition
ECM1 p.Arg53Ter Pathogenic ★★ same condition
ECM1 p.Cys269Tyr Pathogenic/Likely pathogenic ★★ same condition
ECM1 c.122-3T>G Uncertain significance ★★ same condition
ECM1 p.Pro169Ala Uncertain significance ★★ ⚠ same condition
ECM1 p.Ser250Leu Uncertain significance ★★ ⚠ same condition
ECM1 c.1083+10C>T Benign/Likely benign ★★ same condition
ECM1 p.Asp367Val Benign/Likely benign ★★ 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-arg254ter (accessed [today's date]).

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