Is E2F5 p.Pro27Leu (c.80C>T) pathogenic?

E2F5 p.Pro27Leu (c.80C>T) is classified Uncertain significance in E2F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely benign (0.1265); Very rare (popmax 0.00338%, afr).

How common is E2F5 p.Pro27Leu (c.80C>T) in the general population?

E2F5 p.Pro27Leu (c.80C>T) is very rare (popmax 0.00338%, afr) (gnomAD).

What do computational predictors say about E2F5 p.Pro27Leu (c.80C>T)?

AlphaMissense predicts likely benign (score 0.1265) — an in-silico prediction, not a clinical call.

E2F5 p.Pro27Leu

c.80C>T · VCV4015832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1265	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -9.32	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 3.4	GERP -0.31, phastCons 0.088
Regional constraint	o/e 0.90	unconstrained · MANE · 36 kb · p 0.039 · regional, not allelic
Overall
CADD	16.39	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 0.00338% African / African-American · 2/59,170 alleles

Filtering AF 0.000561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000323% 3/929,560 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00338%	29,585
Remaining individualsnot grpmax-eligible	0.00284%	35,204

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: E2F5
Protein: p.Pro27Leu
Coding: c.80C>T
MANE Select: NM_001951
Type: single nucleotide variant
Location: chr8:85177500 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 1 PDB
Residue 27: the 'disordered' region

Full E2F5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F5 p.Ala192Ser Uncertain significance ★ ⚠ same type
E2F5 p.Ala295Glu Uncertain significance ★ ⚠ same type
E2F5 p.Ala44Thr Uncertain significance ★ ⚠ same type
E2F5 p.Ala44Val Uncertain significance ★ ⚠ same type
E2F5 p.Ala78Glu Uncertain significance ★ ⚠ same type
E2F5 p.Asn183Lys Uncertain significance ★ ⚠ same type
E2F5 p.Asp163Gly Uncertain significance ★ ⚠ same type
E2F5 p.Asp177Glu 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/e2f5-p-pro27leu (accessed [today's date]).

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