Is E2F4 p.Ala138Val (c.413C>T) pathogenic?

E2F4 p.Ala138Val (c.413C>T) is classified Uncertain significance in E2F4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9258); Ultra-rare (popmax 0.011%, sas).

How common is E2F4 p.Ala138Val (c.413C>T) in the general population?

E2F4 p.Ala138Val (c.413C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about E2F4 p.Ala138Val (c.413C>T)?

AlphaMissense predicts likely pathogenic (score 0.9258) — an in-silico prediction, not a clinical call.

E2F4 p.Ala138Val

c.413C>T · VCV4246121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9258	likely pathogenic
REVEL	0.691	pathogenic-leaning
SaProt	LLR -11.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 2,127 bp · p 1.9e-05 · regional, not allelic
Overall
CADD	29.4	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 0.011% South Asian · 10/91,084 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000889% 13/1,461,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000169%	590,019

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: E2F4
Protein: p.Ala138Val
Coding: c.413C>T
MANE Select: NM_001950
Type: single nucleotide variant
Location: chr16:67193477 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 65.56 · 2 PDB
Residue 138: the 'dimerization' region

Full E2F4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F4 p.Ala150Thr Uncertain significance ★ ⚠ same type
E2F4 p.Ala239Gly Uncertain significance ★ ⚠ same type
E2F4 p.Ala239Pro Uncertain significance ★ ⚠ same type
E2F4 p.Ala2Gly Uncertain significance ★ ⚠ same type
E2F4 p.Ala340Ser Uncertain significance ★ ⚠ same type
E2F4 p.Ala4Pro Uncertain significance ★ ⚠ same type
E2F4 p.Arg126Gln Uncertain significance ★ ⚠ same type
E2F4 p.Arg241Cys 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/e2f4-p-ala138val (accessed [today's date]).

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