Is ECEL1 p.Phe457Val (c.1369T>G) pathogenic?

ECEL1 p.Phe457Val (c.1369T>G) is classified Likely pathogenic in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-22). AlphaMissense: likely pathogenic (0.9938); Very rare (popmax 0.00424%, nfe); Associated with distal arthrogryposis type 5D.

What condition is associated with ECEL1 p.Phe457Val (c.1369T>G)?

ECEL1 p.Phe457Val (c.1369T>G) is associated with distal arthrogryposis type 5D (ClinVar).

How common is ECEL1 p.Phe457Val (c.1369T>G) in the general population?

ECEL1 p.Phe457Val (c.1369T>G) is very rare (popmax 0.00424%, nfe) (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.Phe457Val (c.1369T>G)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

ECEL1 p.Phe457Val

c.1369T>G · rs778750904 · VCV2412779

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal arthrogryposis type 5D

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic ✓ concordant with ClinVar · top 5% in ECEL1
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -11.60	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	31.0	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 0.00424% European (non-Finnish) · 50/1,178,340 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00341% 55/1,611,624 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,792
European (non-Finnish)grpmax	0.00424%	23,567
African / African-American	0.00267%	37,453

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe457Val
Coding: c.1369T>G
MANE Select: NM_004826
dbSNP: rs778750904
Type: single nucleotide variant
Location: chr2:232484039 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 457: 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-phe457val (accessed [today's date]).

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