Is E2F6 p.Pro29Leu (c.86C>T) pathogenic?

E2F6 p.Pro29Leu (c.86C>T) is classified Uncertain significance in E2F6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-27). AlphaMissense: likely benign (0.2723); Very rare (popmax 8.51e-05%, nfe).

How common is E2F6 p.Pro29Leu (c.86C>T) in the general population?

E2F6 p.Pro29Leu (c.86C>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about E2F6 p.Pro29Leu (c.86C>T)?

AlphaMissense predicts likely benign (score 0.2723) — an in-silico prediction, not a clinical call.

E2F6 p.Pro29Leu

c.86C>T · rs1672162016 · VCV2304013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2723	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.44, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 19 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	23.2	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 8.51e-05% European (non-Finnish) · 1/1,174,606 alleles

Overall 6.9e-05% 1/1,448,506 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.Pro29Leu
Coding: c.86C>T
MANE Select: NM_198256
dbSNP: rs1672162016
Type: single nucleotide variant
Location: chr2:11465794 (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.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-pro29leu (accessed [today's date]).

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