Is ECEL1 p.Val774Met (c.2320G>A) pathogenic?

ECEL1 p.Val774Met (c.2320G>A) is classified Uncertain significance in ECEL1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-07). AlphaMissense: likely pathogenic (0.7555); Ultra-rare (popmax 0.02%, afr); Associated with distal arthrogryposis type 5D.

What condition is associated with ECEL1 p.Val774Met (c.2320G>A)?

ECEL1 p.Val774Met (c.2320G>A) is associated with distal arthrogryposis type 5D (ClinVar).

How common is ECEL1 p.Val774Met (c.2320G>A) in the general population?

ECEL1 p.Val774Met (c.2320G>A) is ultra-rare (popmax 0.02%, afr) (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.Val774Met (c.2320G>A)?

AlphaMissense predicts likely pathogenic (score 0.7555) — an in-silico prediction, not a clinical call.

ECEL1 p.Val774Met

c.2320G>A · rs149447864 · VCV2256361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal arthrogryposis type 5D

Computational evidence

Protein change
AlphaMissense	0.7555	likely pathogenic
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -8.15	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 5.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	28.2	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 0.02% African / African-American · 15/74,902 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0132% 213/1,613,530 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,993
Finnishnot grpmax-eligible	0.0172%	5,810
Admixed American	0.0167%	5,998
Middle Eastern	0.0165%	6,056
European (non-Finnish)	0.0141%	7,107
Remaining individualsnot grpmax-eligible	0.0096%	10,413
South Asian	0.00329%	30,354
East Asian	0.00223%	44,834

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.Val774Met
Coding: c.2320G>A
MANE Select: NM_004826
dbSNP: rs149447864
Type: single nucleotide variant
Location: chr2:232480161 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 774: 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-val774met (accessed [today's date]).

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