Is E4F1 p.Pro625Leu (c.1874C>T) pathogenic?

E4F1 p.Pro625Leu (c.1874C>T) is classified Uncertain significance in E4F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.3322); Very rare (popmax 0.00135%, afr).

How common is E4F1 p.Pro625Leu (c.1874C>T) in the general population?

E4F1 p.Pro625Leu (c.1874C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about E4F1 p.Pro625Leu (c.1874C>T)?

AlphaMissense predicts likely benign (score 0.3322) — an in-silico prediction, not a clinical call.

E4F1 p.Pro625Leu

c.1874C>T · VCV4015874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3322	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,400 bp · p 0.81 · regional, not allelic
Overall
CADD	24.0	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 0.00135% African / African-American · 1/74,102 alleles

Filtering AF 0.000186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000508% 8/1,576,296 alleles · very rare exomes 6/1,424,090 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,102
South Asian	0.00115%	86,970
European (non-Finnish)	0.000517%	193,479

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.Pro625Leu
Coding: c.1874C>T
MANE Select: NM_004424
Type: single nucleotide variant
Location: chr16:2234940 (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-pro625leu (accessed [today's date]).

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