Is E2F8 p.Ser655Pro (c.1963T>C) pathogenic?

E2F8 p.Ser655Pro (c.1963T>C) is classified Uncertain significance in E2F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely benign (0.06); Ultra-rare (popmax 0.0966%, sas).

How common is E2F8 p.Ser655Pro (c.1963T>C) in the general population?

E2F8 p.Ser655Pro (c.1963T>C) is ultra-rare (popmax 0.0966%, sas) (gnomAD).

What do computational predictors say about E2F8 p.Ser655Pro (c.1963T>C)?

AlphaMissense predicts likely benign (score 0.06) — an in-silico prediction, not a clinical call.

E2F8 p.Ser655Pro

c.1963T>C · rs574624357 · VCV2399288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.06 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0966%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.06	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 0.95
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	16.77	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 0.0966% South Asian · 88/91,082 alleles

Filtering AF 0.0803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.00576% 93/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0966%	1,035
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	8.47e-05%	1,180,022

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.Ser655Pro
Coding: c.1963T>C
dbSNP: rs574624357
Type: single nucleotide variant
Location: chr11:19225795 (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-ser655pro (accessed [today's date]).

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