Is ECE1 p.Gly293Ser (c.877G>A) pathogenic?

ECE1 p.Gly293Ser (c.877G>A) is classified Uncertain significance in ECE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.2247); Ultra-rare (popmax 0.0165%, mid); Associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction.

What condition is associated with ECE1 p.Gly293Ser (c.877G>A)?

ECE1 p.Gly293Ser (c.877G>A) is associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction (ClinVar).

How common is ECE1 p.Gly293Ser (c.877G>A) in the general population?

ECE1 p.Gly293Ser (c.877G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ECE1 p.Gly293Ser (c.877G>A)?

AlphaMissense predicts likely benign (score 0.2247) — an in-silico prediction, not a clinical call.

ECE1 p.Gly293Ser

c.877G>A · rs145311594 · VCV1342525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hirschsprung disease, cardiac defects, and autonomic dysfunction

Computational evidence

Protein change
AlphaMissense	0.2247	likely benign
REVEL	0.735	pathogenic-leaning
SaProt	LLR -8.91	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 11 kb · p 3.1e-08 · regional, not allelic
Overall
CADD	27.2	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 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.00931% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00874%

Overall 0.00851% 137/1,609,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,072
Remaining individualsnot grpmax-eligible	0.0128%	7,784
European (non-Finnish)	0.0109%	9,188

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: ECE1
Protein: p.Gly293Ser
Coding: c.877G>A
MANE Select: NM_001397
dbSNP: rs145311594
Type: single nucleotide variant
Location: chr1:21256090 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 293: a disulfide bond; the peptidase m13 domain

Full ECE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hirschsprung disease, cardiac defects, and autonomic dysfunction — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ECE1 p.Thr312Met Uncertain significance ★★ ⚠ same condition
ECE1 p.Gly656Arg Likely pathogenic ★ ⚠ same condition
ECE1 c.1849+4C>T Uncertain significance ★ same condition
ECE1 p.Arg754Cys Pathogenic ⚠ same condition
ECE1 c.1020+15G>A Benign ★★ same type
ECE1 c.1164-5C>T Benign ★★ same type
ECE1 c.1278+7C>T Benign ★★ same type
ECE1 c.1782-4C>A Benign ★★ same type

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/ece1-p-gly293ser (accessed [today's date]).

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