Is ECM1 p.Pro169Ala (c.505C>G) pathogenic?

ECM1 p.Pro169Ala (c.505C>G) is classified Uncertain significance in ECM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.3614); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with ECM1 p.Pro169Ala (c.505C>G)?

ECM1 p.Pro169Ala (c.505C>G) is associated with Inborn genetic diseases, lipoid proteinosis (ClinVar).

How common is ECM1 p.Pro169Ala (c.505C>G) in the general population?

ECM1 p.Pro169Ala (c.505C>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about ECM1 p.Pro169Ala (c.505C>G)?

AlphaMissense predicts ambiguous (score 0.3614) — an in-silico prediction, not a clinical call.

ECM1 p.Pro169Ala

c.505C>G · rs41264471 · VCV916209

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3614	ambiguous
REVEL	0.578	indeterminate
SaProt	LLR -7.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.78, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,254 bp · p 0.14 · regional, not allelic
Overall
CADD	24.2	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 0.0227% African / African-American · 17/75,052 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00725% 117/1,614,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,415
Admixed American	0.0217%	4,617
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,945
South Asian	0.00878%	11,386
European (non-Finnish)	0.00568%	17,612
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Finnishnot grpmax-eligible	0.00156%	64,038

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.Pro169Ala
Coding: c.505C>G
MANE Select: NM_004425
dbSNP: rs41264471
Type: single nucleotide variant
Location: chr1:150510995 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.05
Residue 169: the 'disordered' region; the '2 x approximate repeats' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lipoid proteinosis

Similar variants

ECM1 p.Pro169Ser Uncertain significance ★ ⚠ same residue
ECM1 p.Arg254Ter Pathogenic ★★ same condition
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.Arg185His Uncertain significance ★★ ⚠ same condition
ECM1 p.Asn324His Uncertain significance ★★ ⚠ 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-pro169ala (accessed [today's date]).

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