Is E4F1 p.Val635Met (c.1903G>A) pathogenic?

E4F1 p.Val635Met (c.1903G>A) is classified Uncertain significance in E4F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.1849); Ultra-rare (popmax 0.0361%, afr).

How common is E4F1 p.Val635Met (c.1903G>A) in the general population?

E4F1 p.Val635Met (c.1903G>A) is ultra-rare (popmax 0.0361%, afr) (gnomAD).

What do computational predictors say about E4F1 p.Val635Met (c.1903G>A)?

AlphaMissense predicts likely benign (score 0.1849) — an in-silico prediction, not a clinical call.

E4F1 p.Val635Met

c.1903G>A · rs372658146 · VCV2271593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1849	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.37	donor gain · deltas
Constraint at this position
Conservation	phyloP 4.4	GERP -2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,400 bp · p 0.81 · regional, not allelic
Overall
CADD	24.5	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 0.0361% African / African-American · 27/74,780 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.0043% 69/1,604,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
African / African-Americangrpmax	0.0361%	2,770
Middle Eastern	0.0165%	6,074
South Asian	0.00668%	14,976
Remaining individualsnot grpmax-eligible	0.00483%	20,695
Finnishnot grpmax-eligible	0.00322%	31,047
European (non-Finnish)	0.00238%	41,993
Admixed American	0.00171%	58,622

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: E4F1
Protein: p.Val635Met
Coding: c.1903G>A
MANE Select: NM_004424
dbSNP: rs372658146
Type: single nucleotide variant
Location: chr16:2234969 (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.Val635Ala Uncertain significance ★ ⚠ same residue
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

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-val635met (accessed [today's date]).

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