Is ERI2 p.Arg220Trp (c.658C>T) pathogenic?

ERI2 p.Arg220Trp (c.658C>T) is classified Uncertain significance in ERI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: ambiguous (0.4724); Ultra-rare (popmax 0.0593%, sas).

How common is ERI2 p.Arg220Trp (c.658C>T) in the general population?

ERI2 p.Arg220Trp (c.658C>T) is ultra-rare (popmax 0.0593%, sas) (gnomAD).

What do computational predictors say about ERI2 p.Arg220Trp (c.658C>T)?

AlphaMissense predicts ambiguous (score 0.4724) — an in-silico prediction, not a clinical call.

ERI2 p.Arg220Trp

c.658C>T · VCV4019459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, sas)

Computational evidence

Protein change
AlphaMissense	0.4724	ambiguous
REVEL	0.359	indeterminate
SaProt	LLR -12.47	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,703 bp · p 0.00034 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0593% South Asian · 54/91,040 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0421%

Overall 0.0049% 79/1,613,536 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0593%	1,686
East Asian	0.0111%	8,971
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.00267%	37,510
Admixed American	0.00167%	59,974
European (non-Finnish)	0.0011%	90,738

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: ERI2
Protein: p.Arg220Trp
Coding: c.658C>T
MANE Select: NM_001142725
Type: single nucleotide variant
Location: chr16:20799337 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.66 · 2 PDB
Residue 220: the exonuclease domain; an α-helix

Full ERI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSM3 p.Asn444His Uncertain significance ★ ⚠ same type
ACSM3 p.Gly260Ala Uncertain significance ★ ⚠ same type
ACSM3 p.Pro268Arg Uncertain significance ★ ⚠ same type
ACSM3 p.Trp273Arg Uncertain significance ★ ⚠ same type
ACSM3 p.Tyr457Cys Uncertain significance ★ ⚠ same type
ERI2 p.Ala102Ser Uncertain significance ★ ⚠ same type
ERI2 p.Ala19Val Uncertain significance ★ ⚠ same type
ERI2 p.Ala200Val 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/eri2-p-arg220trp (accessed [today's date]).

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