Is ERI1 p.Arg261Trp (c.781C>T) pathogenic?

ERI1 p.Arg261Trp (c.781C>T) is classified Uncertain significance in ERI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9797); Very rare (popmax 0.00451%, nfe).

How common is ERI1 p.Arg261Trp (c.781C>T) in the general population?

ERI1 p.Arg261Trp (c.781C>T) is very rare (popmax 0.00451%, nfe) (gnomAD).

What do computational predictors say about ERI1 p.Arg261Trp (c.781C>T)?

AlphaMissense predicts likely pathogenic (score 0.9797) — an in-silico prediction, not a clinical call.

ERI1 p.Arg261Trp

c.781C>T · VCV4665119

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00451%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9797	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -17.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 27 kb · p 9.3e-16 · regional, not allelic
Overall
CADD	29.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00451% European (non-Finnish) · 53/1,175,192 alleles

Filtering AF 0.00352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.00356% 57/1,603,194 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00451%	22,173
East Asian	0.00225%	44,422
Remaining individualsnot grpmax-eligible	0.00161%	62,044
Finnishnot grpmax-eligible	0.00157%	63,750
African / African-American	0.00134%	74,412

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: ERI1
Protein: p.Arg261Trp
Coding: c.781C>T
MANE Select: NM_153332
Type: single nucleotide variant
Location: chr8:9020438 (GRCh38)
Gene constraint: LOEUF 1.526 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.04 · 5 PDB
Residue 261: a UniProt-annotated variant site (in semdgc; likely pathogenic); a UniProt-annotated variant site (in hxal; likely pathogenic); the exonuclease domain; an α-helix

Full ERI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERI1 p.Ser333Tyr Uncertain significance ★★ ⚠ same type
ERI1 p.Thr221Ala Uncertain significance ★★ ⚠ same type
ERI1 p.Arg291= Benign ★★ same type
ERI1 p.Arg304Ter Likely pathogenic ★ same type
ERI1 p.Asp134Gly Likely pathogenic ★ same type
ERI1 p.Asp298Gly Likely pathogenic ★ same type
ERI1 p.Gln244Ter Likely pathogenic ★ same type
ERI1 p.Glu150Asp Likely pathogenic ★ 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/eri1-p-arg261trp (accessed [today's date]).

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