Is E2F6 p.His123Arg (c.368A>G) pathogenic?

E2F6 p.His123Arg (c.368A>G) is classified Uncertain significance in E2F6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: ambiguous (0.497); Very rare (popmax 8.47e-05%, nfe).

How common is E2F6 p.His123Arg (c.368A>G) in the general population?

E2F6 p.His123Arg (c.368A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about E2F6 p.His123Arg (c.368A>G)?

AlphaMissense predicts ambiguous (score 0.497) — an in-silico prediction, not a clinical call.

E2F6 p.His123Arg

c.368A>G · VCV4662791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.497	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -8.60	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 19 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	21.0	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 8.47e-05% European (non-Finnish) · 1/1,179,986 alleles

Overall 6.84e-05% 1/1,461,736 alleles · very 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: E2F6
Protein: p.His123Arg
Coding: c.368A>G
MANE Select: NM_198256
Type: single nucleotide variant
Location: chr2:11453594 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.37
Residue 123: a DNA-binding 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-his123arg (accessed [today's date]).

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