Is E4F1 p.Leu37Phe (c.111G>C) pathogenic?

E4F1 p.Leu37Phe (c.111G>C) is classified Uncertain significance in E4F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.1133); Very rare (popmax 0.00388%, amr).

How common is E4F1 p.Leu37Phe (c.111G>C) in the general population?

E4F1 p.Leu37Phe (c.111G>C) is very rare (popmax 0.00388%, amr) (gnomAD).

What do computational predictors say about E4F1 p.Leu37Phe (c.111G>C)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

E4F1 p.Leu37Phe

c.111G>C · rs1043442719 · VCV3086786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00388%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -8.68	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 2	GERP 0.78, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,165 bp · p 0.86 · regional, not allelic
Overall
CADD	15.22	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 0.00388% Admixed American · 2/51,500 alleles

Filtering AF 0.000644% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000241%

Overall 0.000194% 3/1,543,688 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00388%	25,750
Remaining individualsnot grpmax-eligible	0.00168%	59,672

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: E4F1
Protein: p.Leu37Phe
Coding: c.111G>C
MANE Select: NM_004424
dbSNP: rs1043442719
Type: single nucleotide variant
Location: chr16:2223724 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.68

Full E4F1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E4F1 p.Arg490His Uncertain significance ★★ ⚠ same type
E4F1 p.Lys144Gln Likely pathogenic ★ ⚠ same type
E4F1 p.Ala124Val Uncertain significance ★ ⚠ same type
E4F1 p.Ala152Val Uncertain significance ★ ⚠ same type
E4F1 p.Ala15Thr Uncertain significance ★ ⚠ same type
E4F1 p.Ala21Asp Uncertain significance ★ ⚠ same type
E4F1 p.Ala21Ser Uncertain significance ★ ⚠ same type
E4F1 p.Ala292Thr 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/e4f1-p-leu37phe (accessed [today's date]).

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