Is ECM1 p.Pro78fs (c.233del) pathogenic?

ECM1 p.Pro78fs (c.233del) is classified Pathogenic/Likely pathogenic in ECM1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-10). Ultra-rare (popmax 0.0147%, nfe); Associated with lipoid proteinosis.

What condition is associated with ECM1 p.Pro78fs (c.233del)?

ECM1 p.Pro78fs (c.233del) is associated with lipoid proteinosis (ClinVar).

How common is ECM1 p.Pro78fs (c.233del) in the general population?

ECM1 p.Pro78fs (c.233del) is ultra-rare (popmax 0.0147%, nfe) (gnomAD).

ECM1 p.Pro78fs

c.233del · rs768474010 · VCV1034085

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, nfe)

Conditions

lipoid proteinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.44, phastCons 0.99
Overall
CADD	22.6	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 0.0147% European (non-Finnish) · 173/1,179,968 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.0126% 203/1,613,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0312%	3,201
European (non-Finnish)grpmax	0.0147%	6,821
Remaining individualsnot grpmax-eligible	0.0128%	7,810
African / African-American	0.00134%	74,896
South Asian	0.0011%	91,078

Finnish 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.Pro78fs
Coding: c.233del
MANE Select: NM_004425
dbSNP: rs768474010
Type: Deletion
Location: chr1:150509927 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 78: the 'disordered' 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.Pro78Ser Uncertain significance ★★ ⚠ same residue
ECM1 c.1304+33_*300del Pathogenic ★ same condition
ECM1 p.Ala17fs Likely pathogenic ★ same condition
ECM1 p.Ala484fs Pathogenic ★ same condition
ECM1 p.Arg171fs Pathogenic ★ same condition
ECM1 p.Arg430fs Pathogenic ★ same condition
ECM1 p.Gln340fs Likely pathogenic ★ same condition
ECM1 p.Ser48fs 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-pro78fs (accessed [today's date]).

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