Is ECEL1 p.Ser186Trp (c.557C>G) pathogenic?

ECEL1 p.Ser186Trp (c.557C>G) is classified Conflicting classifications of pathogenicity in ECEL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-20). AlphaMissense: likely pathogenic (0.9901); Very rare (popmax 0.00172%, amr); Associated with distal arthrogryposis type 5D.

What condition is associated with ECEL1 p.Ser186Trp (c.557C>G)?

ECEL1 p.Ser186Trp (c.557C>G) is associated with distal arthrogryposis type 5D (ClinVar).

How common is ECEL1 p.Ser186Trp (c.557C>G) in the general population?

ECEL1 p.Ser186Trp (c.557C>G) is very rare (popmax 0.00172%, amr) (gnomAD).

How is Distal arthrogryposis type 5D inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ECEL1 p.Ser186Trp (c.557C>G)?

AlphaMissense predicts likely pathogenic (score 0.9901) — an in-silico prediction, not a clinical call.

ECEL1 p.Ser186Trp

c.557C>G · rs1176131791 · VCV1685759

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal arthrogryposis type 5D

Computational evidence

Protein change
AlphaMissense	0.9901	likely pathogenic · top 6% in ECEL1
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -17.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	32.0	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 0.00172% Admixed American · 1/58,052 alleles

Overall 0.000208% 3/1,442,358 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00172%	58,052
African / African-American	0.00134%	74,592
European (non-Finnish)	8.53e-05%	1,171,989

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.Ser186Trp
Coding: c.557C>G
MANE Select: NM_004826
dbSNP: rs1176131791
Type: single nucleotide variant
Location: chr2:232486097 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 186: a disulfide bond; the peptidase m13 domain

Full ECEL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

distal arthrogryposis type 5D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Distal arthrogryposis type 5D (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

ECEL1 c.1685+1G>A Pathogenic ★★ same condition
ECEL1 c.2151+2T>C Likely pathogenic ★★ same condition
ECEL1 c.966+1G>A Pathogenic ★★ same condition
ECEL1 p.Ala675Thr Pathogenic ★★ same condition
ECEL1 p.Arg333Ter Pathogenic ★★ same condition
ECEL1 p.Arg395Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECEL1 p.Arg418Cys Likely pathogenic ★★ same condition
ECEL1 p.Gln435Ter Pathogenic/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/ecel1-p-ser186trp (accessed [today's date]).

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