Is ERI1 p.Ser89Ala (c.265T>G) pathogenic?

ERI1 p.Ser89Ala (c.265T>G) is classified Uncertain significance in ERI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.0552); Ultra-rare (popmax 0.046%, afr).

How common is ERI1 p.Ser89Ala (c.265T>G) in the general population?

ERI1 p.Ser89Ala (c.265T>G) is ultra-rare (popmax 0.046%, afr) (gnomAD).

What do computational predictors say about ERI1 p.Ser89Ala (c.265T>G)?

AlphaMissense predicts likely benign (score 0.0552) — an in-silico prediction, not a clinical call.

ERI1 p.Ser89Ala

c.265T>G · rs377678941 · VCV2364676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0552 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.046%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0552	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 27 kb · p 9.3e-16 · regional, not allelic
Overall
CADD	18.87	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.046% African / African-American · 34/73,876 alleles

Filtering AF 0.0338% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.0022% 35/1,594,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.046%	2,173
Admixed American	0.0018%	55,518

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.Ser89Ala
Coding: c.265T>G
MANE Select: NM_153332
dbSNP: rs377678941
Type: single nucleotide variant
Location: chr8:9008126 (GRCh38)
Gene constraint: LOEUF 1.526 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.04 · 5 PDB
Residue 89: the sap domain; a UniProt-annotated variant site (in semdgc; likely pathogenic); 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-ser89ala (accessed [today's date]).

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