Is E2F8 p.Phe253Cys (c.758T>G) pathogenic?

E2F8 p.Phe253Cys (c.758T>G) is classified Uncertain significance in E2F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: ambiguous (0.5209); Ultra-rare (popmax 0.0695%, sas).

How common is E2F8 p.Phe253Cys (c.758T>G) in the general population?

E2F8 p.Phe253Cys (c.758T>G) is ultra-rare (popmax 0.0695%, sas) (gnomAD).

What do computational predictors say about E2F8 p.Phe253Cys (c.758T>G)?

AlphaMissense predicts ambiguous (score 0.5209) — an in-silico prediction, not a clinical call.

E2F8 p.Phe253Cys

c.758T>G · rs569729834 · VCV3086783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5209 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0695%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5209	ambiguous
REVEL	0.161	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0695% South Asian · 63/90,624 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0508%

Overall 0.00398% 64/1,609,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0695%	1,438
Remaining individualsnot grpmax-eligible	0.00161%	62,282

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.Phe253Cys
Coding: c.758T>G
dbSNP: rs569729834
Type: single nucleotide variant
Location: chr11:19234752 (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-phe253cys (accessed [today's date]).

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