Is E2F8 p.Ser615Pro (c.1843T>C) pathogenic?

E2F8 p.Ser615Pro (c.1843T>C) is classified Uncertain significance in E2F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.0039%, nfe).

How common is E2F8 p.Ser615Pro (c.1843T>C) in the general population?

E2F8 p.Ser615Pro (c.1843T>C) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about E2F8 p.Ser615Pro (c.1843T>C)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

E2F8 p.Ser615Pro

c.1843T>C · rs529723766 · VCV2227241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 2.7, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	15.37	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 0.0039% European (non-Finnish) · 46/1,179,998 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00304% 49/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,652
African / African-American	0.00267%	37,457
Admixed American	0.00167%	59,974

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.Ser615Pro
Coding: c.1843T>C
MANE Select: NM_024680
dbSNP: rs529723766
Type: single nucleotide variant
Location: chr11:19229504 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.43 (gnomAD)
Structure: AlphaFold pLDDT 54.02 · 1 PDB
Residue 615: the 'disordered' region

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

Similar variants

E2F8 p.Ala585Gly Uncertain significance ★ ⚠ same type
E2F8 p.Asp612Tyr Uncertain significance ★ ⚠ same type
E2F8 p.Gln856Arg Uncertain significance ★ ⚠ same type
E2F8 p.Glu611Lys Uncertain significance ★ ⚠ same type
E2F8 p.Ile726Thr Uncertain significance ★ ⚠ same type
E2F8 p.Leu859Pro Uncertain significance ★ ⚠ same type
E2F8 p.Lys49Arg Uncertain significance ★ ⚠ same type
E2F8 p.Phe853Leu Uncertain significance ★ ⚠ same type

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-ser615pro (accessed [today's date]).

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