Is EIF3A p.Ser488Phe (c.1463C>T) pathogenic?

EIF3A p.Ser488Phe (c.1463C>T) is classified Uncertain significance in EIF3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.6485); Very rare (popmax 0.00835%, nfe).

How common is EIF3A p.Ser488Phe (c.1463C>T) in the general population?

EIF3A p.Ser488Phe (c.1463C>T) is very rare (popmax 0.00835%, nfe) (gnomAD).

What do computational predictors say about EIF3A p.Ser488Phe (c.1463C>T)?

AlphaMissense predicts likely pathogenic (score 0.6485) — an in-silico prediction, not a clinical call.

EIF3A p.Ser488Phe

c.1463C>T · VCV4017145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00835%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6485	likely pathogenic
REVEL	0.291	indeterminate
SaProt	LLR -10.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 12 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	27.6	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 0.00835% European (non-Finnish) · 98/1,173,604 alleles

Filtering AF 0.00701% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00644%

Overall 0.00619% 99/1,599,010 alleles · very rare exomes 98/1,446,690 · genomes 1/152,320 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00835%	11,976
South Asian	0.00113%	88,556

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.Ser488Phe
Coding: c.1463C>T
MANE Select: NM_003750
Type: single nucleotide variant
Location: chr10:119059378 (GRCh38)
Gene constraint: LOEUF 0.18 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.62 · 30 PDB
Residue 488: the pci domain; a turn

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

Similar variants

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
EIF3A p.Ala181Gly 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-ser488phe (accessed [today's date]).

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