Is ECEL1 p.Arg333Ter (c.997C>T) pathogenic?

ECEL1 p.Arg333Ter (c.997C>T) is classified Pathogenic in ECEL1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-03-13). Ultra-rare (popmax 0.0427%, afr); Associated with distal arthrogryposis type 5D.

What condition is associated with ECEL1 p.Arg333Ter (c.997C>T)?

ECEL1 p.Arg333Ter (c.997C>T) is associated with distal arthrogryposis type 5D (ClinVar).

How common is ECEL1 p.Arg333Ter (c.997C>T) in the general population?

ECEL1 p.Arg333Ter (c.997C>T) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

How is Distal arthrogryposis type 5D inherited?

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

ECEL1 p.Arg333Ter

c.997C>T · rs370167241 · VCV210910

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Conditions

distal arthrogryposis type 5D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.98, phastCons 0.39
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0427% African / African-American · 32/74,902 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00248% 40/1,613,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,341
South Asian	0.0022%	45,544
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000339%	294,997

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.Arg333Ter
Coding: c.997C>T
MANE Select: NM_004826
dbSNP: rs370167241
Type: single nucleotide variant
Location: chr2:232484863 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 333: 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.Arg395Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECEL1 p.Arg418Cys Likely pathogenic ★★ same condition
ECEL1 p.Gln435Ter Pathogenic/Likely pathogenic ★★ same condition
ECEL1 p.Gly511Ser 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-arg333ter (accessed [today's date]).

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