Is ECEL1 p.Arg756Trp (c.2266C>T) pathogenic?

ECEL1 p.Arg756Trp (c.2266C>T) is classified Uncertain significance in ECEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-09). AlphaMissense: likely benign (0.1672); Ultra-rare (popmax 0.0531%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ECEL1 p.Arg756Trp (c.2266C>T)?

ECEL1 p.Arg756Trp (c.2266C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ECEL1 p.Arg756Trp (c.2266C>T) in the general population?

ECEL1 p.Arg756Trp (c.2266C>T) is ultra-rare (popmax 0.0531%, nfe) (gnomAD).

What do computational predictors say about ECEL1 p.Arg756Trp (c.2266C>T)?

AlphaMissense predicts likely benign (score 0.1672) — an in-silico prediction, not a clinical call.

ECEL1 p.Arg756Trp

c.2266C>T · rs147861587 · VCV1254457

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1672 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0531%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1672	likely benign
REVEL	0.682	pathogenic-leaning
SaProt	LLR -12.92	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.4	GERP 5.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	33.0	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 0.0531% European (non-Finnish) · 626/1,179,984 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0482%

Overall 0.0413% 667/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0531%	1,885
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Finnishnot grpmax-eligible	0.0172%	5,817
African / African-American	0.0133%	7,502
Admixed American	0.005%	20,002
South Asian	0.00439%	22,769

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: ECEL1
Protein: p.Arg756Trp
Coding: c.2266C>T
MANE Select: NM_004826
dbSNP: rs147861587
Type: single nucleotide variant
Location: chr2:232480215 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 756: a disulfide bond; the peptidase m13 domain

Full ECEL1 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

Similar variants

ECEL1 p.Gly209Val Uncertain significance ★★ ⚠ same condition
ECEL1 p.Pro34Ser Uncertain significance ★★ ⚠ same condition
ECEL1 p.Ser44Arg Uncertain significance ★★ ⚠ same condition
ECEL1 p.Arg355Gln Likely benign ★★ same condition
ECEL1 c.1990-6C>T Conflicting classifications of pathogenicity ★ same condition
ECEL1 p.Ala109Val Uncertain significance ★ ⚠ same condition
ECEL1 p.Ala175Thr Uncertain significance ★ ⚠ same condition
ECEL1 p.Ala182Thr 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/ecel1-p-arg756trp (accessed [today's date]).

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