Is CHD2 p.Ser866Leu (c.2597C>T) pathogenic?

CHD2 p.Ser866Leu (c.2597C>T) is classified Conflicting classifications of pathogenicity in CHD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-30). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy 94.

What condition is associated with CHD2 p.Ser866Leu (c.2597C>T)?

CHD2 p.Ser866Leu (c.2597C>T) is associated with developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Ser866Leu (c.2597C>T) in the general population?

CHD2 p.Ser866Leu (c.2597C>T) is absent from gnomAD v4.1 (gnomAD).

How is Lennox-Gastaut syndrome inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHD2 p.Ser866Leu (c.2597C>T)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

CHD2 p.Ser866Leu

c.2597C>T · rs1085308000 · VCV427169

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy 94

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 3% in CHD2
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -17.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 4,305 bp · p 1.3e-19 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHD2
Protein: p.Ser866Leu
Coding: c.2597C>T
MANE Select: NM_001271
dbSNP: rs1085308000
Type: single nucleotide variant
Location: chr15:92978253 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 866: the helicase c-terminal domain; a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance)

Full CHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy 94 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lennox-Gastaut syndrome (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial, Not applicable
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CHD2 p.Ser866Ter Pathogenic ★ same residue
CHD2 p.Ser866= Uncertain significance ★ same residue
CHD2 p.Ser866Pro Uncertain significance ★ ⚠ same residue
CHD2 c.1153+1G>C Pathogenic ★★ same condition
CHD2 c.1809+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD2 c.294+1G>T Likely pathogenic ★★ same condition
CHD2 c.443+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD2 c.693-1G>A Likely pathogenic ★★ same condition

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/chd2-p-ser866leu (accessed [today's date]).

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