Is E2F5 p.Pro39Arg (c.116C>G) pathogenic?

E2F5 p.Pro39Arg (c.116C>G) is classified Uncertain significance in E2F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.1538); Ultra-rare (popmax 0.0141%, nfe).

How common is E2F5 p.Pro39Arg (c.116C>G) in the general population?

E2F5 p.Pro39Arg (c.116C>G) is ultra-rare (popmax 0.0141%, nfe) (gnomAD).

What do computational predictors say about E2F5 p.Pro39Arg (c.116C>G)?

AlphaMissense predicts likely benign (score 0.1538) — an in-silico prediction, not a clinical call.

E2F5 p.Pro39Arg

c.116C>G · VCV3843185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1538 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1538	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -9.31	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 -0.73	GERP -3.4
Regional constraint	o/e 0.90	unconstrained · MANE · 36 kb · p 0.039 · regional, not allelic
Overall
CADD	1.362	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 0.0141% European (non-Finnish) · 136/964,070 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.0115% 137/1,195,248 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0141%	7,089
African / African-American	0.00159%	62,938

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.Pro39Arg
Coding: c.116C>G
MANE Select: NM_001951
Type: single nucleotide variant
Location: chr8:85177536 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 1 PDB
Residue 39: the 'disordered' region

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

Similar variants

E2F5 p.Pro39Leu Uncertain significance ★ ⚠ same residue
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

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-pro39arg (accessed [today's date]).

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