Is E2F8 p.Val459Met (c.1375G>A) pathogenic?

E2F8 p.Val459Met (c.1375G>A) is classified Uncertain significance in E2F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.0769); Ultra-rare (popmax 0.0131%, nfe).

How common is E2F8 p.Val459Met (c.1375G>A) in the general population?

E2F8 p.Val459Met (c.1375G>A) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

What do computational predictors say about E2F8 p.Val459Met (c.1375G>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

E2F8 p.Val459Met

c.1375G>A · rs201330589 · VCV3086772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.23	phastCons 0.012
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	12.01	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 0.0131% European (non-Finnish) · 155/1,179,920 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0104% 168/1,613,716 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.329%	304
European (non-Finnish)grpmax	0.0131%	7,612
African / African-American	0.008%	12,505
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed American	0.00167%	60,012

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val459Met
Coding: c.1375G>A
dbSNP: rs201330589
Type: single nucleotide variant
Location: chr11:19229972 (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-val459met (accessed [today's date]).

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