Is EIF3A p.Arg889His (c.2666G>A) pathogenic?

EIF3A p.Arg889His (c.2666G>A) is classified Uncertain significance in EIF3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.2369); Ultra-rare (popmax 0.0111%, eas).

How common is EIF3A p.Arg889His (c.2666G>A) in the general population?

EIF3A p.Arg889His (c.2666G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about EIF3A p.Arg889His (c.2666G>A)?

AlphaMissense predicts likely benign (score 0.2369) — an in-silico prediction, not a clinical call.

EIF3A p.Arg889His

c.2666G>A · VCV4017153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2369	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0035 · regional, not allelic
Overall
CADD	29.5	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 0.0111% East Asian · 5/44,888 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00298% 48/1,611,330 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0208%	4,800
East Asiangrpmax	0.0111%	8,978
Admixed American	0.00333%	29,998
European (non-Finnish)	0.00221%	45,292
Finnishnot grpmax-eligible	0.00156%	64,020
South Asian	0.0011%	91,020

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EIF3A
Protein: p.Arg889His
Coding: c.2666G>A
MANE Select: NM_003750
Type: single nucleotide variant
Location: chr10:119044135 (GRCh38)
Gene constraint: LOEUF 0.18 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.62 · 30 PDB
Residue 889: the 'disordered' region

Full EIF3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF3A p.Arg889Cys Uncertain significance ★ ⚠ same residue
EIF3A p.Ala1358= Benign ★★ same type
EIF3A p.Arg1046Trp Likely benign ★★ ⚠ same type
EIF3A p.Arg406= Benign/Likely benign ★★ same type
EIF3A p.Arg803Lys Benign ★★ ⚠ same type
EIF3A p.Asp993Glu Benign ★★ ⚠ same type
EIF3A p.Arg1273Ser Likely pathogenic ★ ⚠ same type
EIF3A p.Ala1354Ser 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/eif3a-p-arg889his (accessed [today's date]).

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