Is EIF4E p.Asp125= (c.375C>T) pathogenic?

EIF4E p.Asp125= (c.375C>T) is classified Benign in EIF4E (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). Common (popmax 27.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with EIF4E-related disorder.

What condition is associated with EIF4E p.Asp125= (c.375C>T)?

EIF4E p.Asp125= (c.375C>T) is associated with EIF4E-related disorder (ClinVar).

EIF4E p.Asp125=

Q: How common is EIF4E p.Asp125= (c.375C>T) in the general population?

EIF4E p.Asp125= (c.375C>T) is common (popmax 27.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.375C>T · rs62323192 · VCV3059002

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 27.8%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

EIF4E-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.233	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.6	GERP 0.36, phastCons 1
Overall
CADD	9.172	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.8% European (non-Finnish) · 327,387/1,179,578 alleles

Filtering AF 27.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.6%

Overall 24.4% 393,858/1,613,126 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	31.9%	3
Ashkenazi Jewishnot grpmax-eligible	29.4%	3
European (non-Finnish)grpmax	27.8%	4
Middle Eastern	24.1%	4
Remaining individualsnot grpmax-eligible	23.4%	4
Finnishnot grpmax-eligible	22.3%	4
South Asian	16.4%	6
Admixed American	14.1%	7
African / African-American	5%	20
East Asian	0.158%	632

Amish 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: EIF4E
Protein: p.Asp125=
Coding: c.375C>T
MANE Select: NM_001968
dbSNP: rs62323192
Type: single nucleotide variant
Location: chr4:98887103 (GRCh38)
Gene constraint: LOEUF 0.09 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.48 · 45 PDB
Residue 125: a turn

Full EIF4E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EIF4E-related disorder

Similar variants

EIF4E c.18+10G>T Likely benign same condition
EIF4E c.18+120T>C Benign same condition
EIF4E c.18+1G>T Uncertain significance ★ same type
EIF4E c.399+599C>T Uncertain significance ★ same type
EIF4E p.Ala29Thr Uncertain significance ★ ⚠ same type
EIF4E p.Arg109Leu Uncertain significance ★ ⚠ same type
EIF4E p.Arg181Met Uncertain significance ★ same type
EIF4E p.Asn41Ser 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/eif4e-p-asp125 (accessed [today's date]).

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