Is E2F6 p.Asn108Ser (c.323A>G) pathogenic?

E2F6 p.Asn108Ser (c.323A>G) is classified Uncertain significance in E2F6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely pathogenic (0.7954); Ultra-rare (popmax 0.0164%, mid).

How common is E2F6 p.Asn108Ser (c.323A>G) in the general population?

E2F6 p.Asn108Ser (c.323A>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about E2F6 p.Asn108Ser (c.323A>G)?

AlphaMissense predicts likely pathogenic (score 0.7954) — an in-silico prediction, not a clinical call.

E2F6 p.Asn108Ser

c.323A>G · rs780272589 · VCV2228140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7954 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7954	likely pathogenic
REVEL	0.276	benign-leaning
SaProt	LLR -11.44	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 19 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	21.9	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00118% 19/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.005%	19,998
African / African-American	0.00267%	37,456
South Asian	0.0022%	45,547
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	64,038
European (non-Finnish)	0.000763%	131,116

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.Asn108Ser
Coding: c.323A>G
MANE Select: NM_198256
dbSNP: rs780272589
Type: single nucleotide variant
Location: chr2:11453639 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.37
Residue 108: a DNA-binding region

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

Similar variants

E2F6 p.Asn108Ile Uncertain significance ★ ⚠ same residue
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.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-asn108ser (accessed [today's date]).

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