Is E2F8 p.Pro135Arg (c.404C>G) pathogenic?

E2F8 p.Pro135Arg (c.404C>G) is classified Uncertain significance in E2F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1965); Very rare (popmax 0.01%, amr).

How common is E2F8 p.Pro135Arg (c.404C>G) in the general population?

E2F8 p.Pro135Arg (c.404C>G) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about E2F8 p.Pro135Arg (c.404C>G)?

AlphaMissense predicts likely benign (score 0.1965) — an in-silico prediction, not a clinical call.

E2F8 p.Pro135Arg

c.404C>G · VCV4662804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1965	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	27.2	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 0.01% Admixed American · 6/60,016 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000558% 9/1,614,128 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,003
African / African-American	0.00267%	37,518
European (non-Finnish)	8.47e-05%	1,180,004

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: E2F8
Protein: p.Pro135Arg
Coding: c.404C>G
Type: single nucleotide variant
Location: chr11:19237361 (GRCh38)

Full E2F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/e2f8-p-pro135arg (accessed [today's date]).

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