Is CHD2 p.Ser688Arg (c.2062A>C) pathogenic?

CHD2 p.Ser688Arg (c.2062A>C) is classified Uncertain significance in CHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.8149); Very rare (popmax 0.00989%, sas); Associated with developmental and epileptic encephalopathy 94.

What condition is associated with CHD2 p.Ser688Arg (c.2062A>C)?

CHD2 p.Ser688Arg (c.2062A>C) is associated with developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Ser688Arg (c.2062A>C) in the general population?

CHD2 p.Ser688Arg (c.2062A>C) is very rare (popmax 0.00989%, sas) (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.Ser688Arg (c.2062A>C)?

AlphaMissense predicts likely pathogenic (score 0.8149) — an in-silico prediction, not a clinical call.

CHD2 p.Ser688Arg

c.2062A>C · rs2505515783 · VCV2807742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00989%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

developmental and epileptic encephalopathy 94

Computational evidence

Protein change
AlphaMissense	0.8149	likely pathogenic
REVEL	0.473	indeterminate
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 18 kb · p 1e-19 · regional, not allelic
Overall
CADD	24.2	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 0.00989% South Asian · 9/91,022 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.000558% 9/1,613,266 alleles · very rare exomes 9/1,461,062 · genomes 0/152,204 · joint denominator

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: CHD2
Protein: p.Ser688Arg
Coding: c.2062A>C
MANE Select: NM_001271
dbSNP: rs2505515783
Type: single nucleotide variant
Location: chr15:92967386 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 688: 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 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
CHD2 p.Ala879Val Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Arg1072Ter Pathogenic ★★ same condition
CHD2 p.Arg1137Ter Pathogenic/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-ser688arg (accessed [today's date]).

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