Is E2F6 p.Arg25Trp (c.73C>T) pathogenic?

E2F6 p.Arg25Trp (c.73C>T) is classified Uncertain significance in E2F6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: ambiguous (0.396); Very rare (popmax 0.00226%, eas).

How common is E2F6 p.Arg25Trp (c.73C>T) in the general population?

E2F6 p.Arg25Trp (c.73C>T) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about E2F6 p.Arg25Trp (c.73C>T)?

AlphaMissense predicts ambiguous (score 0.396) — an in-silico prediction, not a clinical call.

E2F6 p.Arg25Trp

c.73C>T · rs1168981860 · VCV2320129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.396	ambiguous
REVEL	0.224	benign-leaning
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP -0.67, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 19 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	25.2	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 0.00226% East Asian · 1/44,228 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00025% 4/1,600,272 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,228
European (non-Finnish)	0.000255%	391,481

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.Arg25Trp
Coding: c.73C>T
MANE Select: NM_198256
dbSNP: rs1168981860
Type: single nucleotide variant
Location: chr2:11465807 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.37

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.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
E2F6 p.Asn31Thr 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-arg25trp (accessed [today's date]).

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