Is E2F5 p.Asp81Ala (c.242A>C) pathogenic?

E2F5 p.Asp81Ala (c.242A>C) is classified Uncertain significance in E2F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.982); Very rare (popmax 0.000594%, nfe).

How common is E2F5 p.Asp81Ala (c.242A>C) in the general population?

E2F5 p.Asp81Ala (c.242A>C) is very rare (popmax 0.000594%, nfe) (gnomAD).

What do computational predictors say about E2F5 p.Asp81Ala (c.242A>C)?

AlphaMissense predicts likely pathogenic (score 0.982) — an in-silico prediction, not a clinical call.

E2F5 p.Asp81Ala

c.242A>C · VCV4246131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.982	likely pathogenic
REVEL	0.365	indeterminate
SaProt	LLR -13.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 36 kb · p 0.039 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000594% European (non-Finnish) · 7/1,179,306 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,460,280 alleles · very rare

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.Asp81Ala
Coding: c.242A>C
MANE Select: NM_001951
Type: single nucleotide variant
Location: chr8:85202154 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 1 PDB
Residue 81: a DNA-binding region; the 'leucine-zipper' region

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

Similar variants

E2F5 p.Asp81Glu Uncertain significance ★ ⚠ same residue
E2F5 p.Asp81Val 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

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-asp81ala (accessed [today's date]).

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