Is EIF3A p.Ser1364Phe (c.4091C>T) pathogenic?

EIF3A p.Ser1364Phe (c.4091C>T) is classified Uncertain significance in EIF3A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: likely benign (0.1918); Very rare (popmax 8.47e-05%, nfe).

How common is EIF3A p.Ser1364Phe (c.4091C>T) in the general population?

EIF3A p.Ser1364Phe (c.4091C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EIF3A p.Ser1364Phe (c.4091C>T)?

AlphaMissense predicts likely benign (score 0.1918) — an in-silico prediction, not a clinical call.

EIF3A p.Ser1364Phe

c.4091C>T · rs754701550 · VCV2307713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1918	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -8.40	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,133 bp · p 0.069 · regional, not allelic
Overall
CADD	21.9	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 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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.Ser1364Phe
Coding: c.4091C>T
MANE Select: NM_003750
dbSNP: rs754701550
Type: single nucleotide variant
Location: chr10:119036097 (GRCh38)
Gene constraint: LOEUF 0.18 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.62 · 30 PDB
Residue 1364: the 'disordered' region; a modified residue (phosphoserine)

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

Similar variants

EIF3A p.Ser1364Cys 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-ser1364phe (accessed [today's date]).

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