Is ECEL1 p.Arg544Cys (c.1630C>T) pathogenic?

ECEL1 p.Arg544Cys (c.1630C>T) is classified Uncertain significance in ECEL1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-12). AlphaMissense: ambiguous (0.3497); Very rare (popmax 0.00223%, eas); Associated with distal arthrogryposis type 5D.

What condition is associated with ECEL1 p.Arg544Cys (c.1630C>T)?

ECEL1 p.Arg544Cys (c.1630C>T) is associated with distal arthrogryposis type 5D (ClinVar).

How common is ECEL1 p.Arg544Cys (c.1630C>T) in the general population?

ECEL1 p.Arg544Cys (c.1630C>T) is very rare (popmax 0.00223%, 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.Arg544Cys (c.1630C>T)?

AlphaMissense predicts ambiguous (score 0.3497) — an in-silico prediction, not a clinical call.

ECEL1 p.Arg544Cys

c.1630C>T · rs753016147 · VCV816801

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

distal arthrogryposis type 5D

Computational evidence

Protein change
AlphaMissense	0.3497	ambiguous
REVEL	0.551	indeterminate
SaProt	LLR -9.48	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	27.1	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 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
European (non-Finnish)	0.00144%	69,415
South Asian	0.0011%	91,080

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.Arg544Cys
Coding: c.1630C>T
MANE Select: NM_004826
dbSNP: rs753016147
Type: single nucleotide variant
Location: chr2:232482906 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 544: 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 p.Arg544His Uncertain significance ★ ⚠ same residue
ECEL1 p.Arg544Leu Uncertain significance ★ ⚠ 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-arg544cys (accessed [today's date]).

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