Is EIF4B p.Ser504Phe (c.1511C>T) pathogenic?

EIF4B p.Ser504Phe (c.1511C>T) is classified Uncertain significance in EIF4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.1097); Ultra-rare (popmax 0.017%, nfe).

How common is EIF4B p.Ser504Phe (c.1511C>T) in the general population?

EIF4B p.Ser504Phe (c.1511C>T) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

What do computational predictors say about EIF4B p.Ser504Phe (c.1511C>T)?

AlphaMissense predicts likely benign (score 0.1097) — an in-silico prediction, not a clinical call.

EIF4B p.Ser504Phe

c.1511C>T · VCV4017233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1097	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -10.47	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 5,675 bp · p 5.7e-08 · regional, not allelic
Overall
CADD	26.5	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 0.017% European (non-Finnish) · 200/1,179,836 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.013% 209/1,613,794 alleles · ultra-rare exomes 197/1,461,598 · genomes 12/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.017%	5,899
Remaining individualsnot grpmax-eligible	0.0112%	8,924
Admixed American	0.00167%	59,982
African / African-American	0.00133%	74,910

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: EIF4B
Protein: p.Ser504Phe
Coding: c.1511C>T
MANE Select: NM_001417
Type: single nucleotide variant
Location: chr12:53037613 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.91 · 3 PDB
Residue 504: a modified residue (phosphoserine); the 'disordered' region

Full EIF4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF4B p.Ala204Gly Uncertain significance ★ ⚠ same type
EIF4B p.Ala364Val Uncertain significance ★ ⚠ same type
EIF4B p.Ala493Thr Uncertain significance ★ ⚠ same type
EIF4B p.Ala5Val Uncertain significance ★ ⚠ same type
EIF4B p.Ala65Ser Uncertain significance ★ ⚠ same type
EIF4B p.Arg202Cys Uncertain significance ★ ⚠ same type
EIF4B p.Arg225Gln Uncertain significance ★ ⚠ same type
EIF4B p.Arg227His 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/eif4b-p-ser504phe (accessed [today's date]).

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