Is E2F6 p.Met153Val (c.457A>G) pathogenic?

E2F6 p.Met153Val (c.457A>G) is classified Uncertain significance in E2F6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely benign (0.1722); Very rare (popmax 0.00669%, amr).

How common is E2F6 p.Met153Val (c.457A>G) in the general population?

E2F6 p.Met153Val (c.457A>G) is very rare (popmax 0.00669%, amr) (gnomAD).

What do computational predictors say about E2F6 p.Met153Val (c.457A>G)?

AlphaMissense predicts likely benign (score 0.1722) — an in-silico prediction, not a clinical call.

E2F6 p.Met153Val

c.457A>G · VCV4662788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1722	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -9.05	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 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 19 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	19.7	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 0.00669% Admixed American · 4/59,758 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000683% 11/1,610,066 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00669%	14,940
South Asian	0.00111%	90,438
European (non-Finnish)	0.00051%	196,270

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: E2F6
Protein: p.Met153Val
Coding: c.457A>G
MANE Select: NM_198256
Type: single nucleotide variant
Location: chr2:11451730 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.37
Residue 153: the 'dimerization' region; the 'leucine-zipper' region

Full E2F6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F6 p.Ala206Thr Uncertain significance ★ ⚠ same type
E2F6 p.Arg25Trp Uncertain significance ★ ⚠ same type
E2F6 p.Arg80Lys Uncertain significance ★ ⚠ same type
E2F6 p.Arg99Gln Uncertain significance ★ ⚠ same type
E2F6 p.Asn108Ile Uncertain significance ★ ⚠ same type
E2F6 p.Asn108Ser Uncertain significance ★ ⚠ same type
E2F6 p.Asn133Asp Uncertain significance ★ ⚠ same type
E2F6 p.Asn228Ser 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/e2f6-p-met153val (accessed [today's date]).

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