Is E2F8 p.Pro45Ser (c.133C>T) pathogenic?

E2F8 p.Pro45Ser (c.133C>T) is classified Uncertain significance in E2F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely pathogenic (0.9423); Ultra-rare (popmax 0.0111%, eas).

How common is E2F8 p.Pro45Ser (c.133C>T) in the general population?

E2F8 p.Pro45Ser (c.133C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about E2F8 p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely pathogenic (score 0.9423) — an in-silico prediction, not a clinical call.

E2F8 p.Pro45Ser

c.133C>T · rs769970471 · VCV2556801

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9423 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9423	likely pathogenic
REVEL	0.485	indeterminate
SaProt	LLR -11.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 6.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	27.6	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 0.0111% East Asian · 5/44,906 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00031% 5/1,614,088 alleles · ultra-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: E2F8
Protein: p.Pro45Ser
Coding: c.133C>T
dbSNP: rs769970471
Type: single nucleotide variant
Location: chr11:19238015 (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-pro45ser (accessed [today's date]).

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