Is ECE2 p.Arg130Trp (c.388C>T) pathogenic?

ECE2 p.Arg130Trp (c.388C>T) is classified Uncertain significance in ECE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.1562); Ultra-rare (popmax 0.0113%, nfe).

How common is ECE2 p.Arg130Trp (c.388C>T) in the general population?

ECE2 p.Arg130Trp (c.388C>T) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about ECE2 p.Arg130Trp (c.388C>T)?

AlphaMissense predicts likely benign (score 0.1562) — an in-silico prediction, not a clinical call.

ECE2 p.Arg130Trp

c.388C>T · rs138696988 · VCV3086919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1562	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -12.73	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP -0.43, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R176W vs ClinVar R130W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0113% European (non-Finnish) · 133/1,180,044 alleles

Filtering AF 0.00969% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0088% 142/1,614,118 alleles · ultra-rare exomes 131/1,461,884 · genomes 11/152,234 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0113%	8,872
Admixed American	0.00666%	15,004
South Asian	0.00329%	30,364
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Arg130Trp
Coding: c.388C>T
MANE Select: NM_001100121
dbSNP: rs138696988
Type: single nucleotide variant
Location: chr3:184277376 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 176 UniProt numbering: the peptidase m13 domain

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

Similar variants

ECE2 p.Arg130Gln Uncertain significance ★ ⚠ same residue
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

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-arg130trp (accessed [today's date]).

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