Is ECE1 p.Ala345Ser (c.1033G>T) pathogenic?

ECE1 p.Ala345Ser (c.1033G>T) is classified Uncertain significance in ECE1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-27). AlphaMissense: likely benign (0.1004); Absent from gnomAD v4.1; Associated with ECE1-related disorder.

What condition is associated with ECE1 p.Ala345Ser (c.1033G>T)?

ECE1 p.Ala345Ser (c.1033G>T) is associated with ECE1-related disorder (ClinVar).

How common is ECE1 p.Ala345Ser (c.1033G>T) in the general population?

ECE1 p.Ala345Ser (c.1033G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ECE1 p.Ala345Ser (c.1033G>T)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

ECE1 p.Ala345Ser

c.1033G>T · VCV3356093

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ECE1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.63, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 11 kb · p 3.1e-08 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ECE1
Protein: p.Ala345Ser
Coding: c.1033G>T
MANE Select: NM_001397
Type: single nucleotide variant
Location: chr1:21247351 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 345: a disulfide bond; the peptidase m13 domain

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

Disease context

ECE1-related disorder

Similar variants

ECE1 c.139-68C>G Uncertain significance same condition
ECE1 c.1488+1G>A Uncertain significance same condition
ECE1 p.Arg618Gln Uncertain significance ⚠ same condition
ECE1 c.139-43G>A Likely benign same condition
ECE1 p.Gly673= Likely benign same condition
ECE1 p.Pro8= Benign same condition
ECE1 p.Thr354Ala Benign same condition
ECE1 p.Thr312Met Uncertain significance ★★ ⚠ 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-ala345ser (accessed [today's date]).

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