Is ECE2 p.Ser629Thr (c.1885T>A) pathogenic?

ECE2 p.Ser629Thr (c.1885T>A) is classified Uncertain significance in ECE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-08). AlphaMissense: likely benign (0.2692); Rare (popmax 0.738%, mid).

How common is ECE2 p.Ser629Thr (c.1885T>A) in the general population?

ECE2 p.Ser629Thr (c.1885T>A) is rare (popmax 0.738%, mid) (gnomAD).

What do computational predictors say about ECE2 p.Ser629Thr (c.1885T>A)?

AlphaMissense predicts likely benign (score 0.2692) — an in-silico prediction, not a clinical call.

ECE2 p.Ser629Thr

c.1885T>A · rs149515968 · VCV2622238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2692 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.738%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2692	likely benign
REVEL	0.534	indeterminate
SaProt	LLR -5.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.64, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	23.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S675T vs ClinVar S629T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.738% Middle Eastern · 44/5,966 alleles

Filtering AF 0.565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.504%

Overall 0.322% 5,146/1,596,128 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.738%	136
European (non-Finnish)	0.383%	261
Remaining individualsnot grpmax-eligible	0.341%	293
Ashkenazi Jewishnot grpmax-eligible	0.302%	332
South Asian	0.244%	410
Admixed American	0.0848%	1,179
African / African-American	0.051%	1,960
Finnishnot grpmax-eligible	0.0362%	2,759

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: ECE2
Protein: p.Ser629Thr
Coding: c.1885T>A
MANE Select: NM_001100121
dbSNP: rs149515968
Type: single nucleotide variant
Location: chr3:184291090 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 629: a disulfide bond; the peptidase m13 domain

Full ECE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECE2 p.Arg453Gln Benign ★★ same type
ECE2 p.Ser400= Benign ★★ same type
ECE2 p.Val248= Benign ★★ same type
EEF1AKMT4-ECE2 p.Val127Ala Benign ★★ ⚠ same type
ECE2 p.Ala338Val Uncertain significance ★ ⚠ same type
ECE2 p.Ala437Thr Uncertain significance ★ ⚠ same type
ECE2 p.Ala575Thr Uncertain significance ★ ⚠ same type
ECE2 p.Ala638Gly 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/ece2-p-ser629thr (accessed [today's date]).

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