Is ECEL1 p.Arg418His (c.1253G>A) pathogenic?

ECEL1 p.Arg418His (c.1253G>A) is classified Likely pathogenic in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). AlphaMissense: ambiguous (0.4996); Ultra-rare (popmax 0.0223%, eas); Associated with distal arthrogryposis type 5D.

What condition is associated with ECEL1 p.Arg418His (c.1253G>A)?

ECEL1 p.Arg418His (c.1253G>A) is associated with distal arthrogryposis type 5D (ClinVar).

How common is ECEL1 p.Arg418His (c.1253G>A) in the general population?

ECEL1 p.Arg418His (c.1253G>A) is ultra-rare (popmax 0.0223%, eas) (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.Arg418His (c.1253G>A)?

AlphaMissense predicts ambiguous (score 0.4996) — an in-silico prediction, not a clinical call.

ECEL1 p.Arg418His

c.1253G>A · rs371924008 · VCV2500295

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

distal arthrogryposis type 5D

Computational evidence

Protein change
AlphaMissense	0.4996	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -10.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 0.46, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	29.5	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 0.0223% East Asian · 10/44,892 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.0013% 21/1,613,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,489
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000763%	131,114

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.Arg418His
Coding: c.1253G>A
MANE Select: NM_004826
dbSNP: rs371924008
Type: single nucleotide variant
Location: chr2:232484155 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 418: a disulfide bond; a UniProt-annotated variant site (in da5d); 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 p.Arg418Cys Likely pathogenic ★★ same residue
ECEL1 p.Arg418Ser Pathogenic same residue
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

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-arg418his (accessed [today's date]).

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