Is ECE2 p.Arg467Trp (c.1399C>T) pathogenic?

ECE2 p.Arg467Trp (c.1399C>T) is classified Uncertain significance in ECE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely pathogenic (0.8148); Very rare (popmax 0.00222%, sas).

How common is ECE2 p.Arg467Trp (c.1399C>T) in the general population?

ECE2 p.Arg467Trp (c.1399C>T) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about ECE2 p.Arg467Trp (c.1399C>T)?

AlphaMissense predicts likely pathogenic (score 0.8148) — an in-silico prediction, not a clinical call.

ECE2 p.Arg467Trp

c.1399C>T · rs565579462 · VCV3086904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8148	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -13.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 0.62, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R513W vs ClinVar R467W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00222% South Asian · 2/90,244 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000651%

Overall 0.00112% 18/1,609,786 alleles · very rare exomes 17/1,457,622 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00222%	45,122
European (non-Finnish)	0.00136%	73,644

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.Arg467Trp
Coding: c.1399C>T
MANE Select: NM_001100121
dbSNP: rs565579462
Type: single nucleotide variant
Location: chr3:184289461 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 513 UniProt numbering: 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-arg467trp (accessed [today's date]).

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