Is CHD2 p.Arg1342Trp (c.4024C>T) pathogenic?

CHD2 p.Arg1342Trp (c.4024C>T) is classified Uncertain significance in CHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: ambiguous (0.5004); Very rare (popmax 0.0011%, nfe); Associated with developmental and epileptic encephalopathy 94.

What condition is associated with CHD2 p.Arg1342Trp (c.4024C>T)?

CHD2 p.Arg1342Trp (c.4024C>T) is associated with developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Arg1342Trp (c.4024C>T) in the general population?

CHD2 p.Arg1342Trp (c.4024C>T) is very rare (popmax 0.0011%, nfe) (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.Arg1342Trp (c.4024C>T)?

AlphaMissense predicts ambiguous (score 0.5004) — an in-silico prediction, not a clinical call.

CHD2 p.Arg1342Trp

c.4024C>T · rs374407665 · VCV2041832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

developmental and epileptic encephalopathy 94

Computational evidence

Protein change
AlphaMissense	0.5004	ambiguous
REVEL	0.68	pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.53, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,067 bp · p 0.73 · regional, not allelic
Overall
CADD	27.5	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 0.0011% European (non-Finnish) · 13/1,177,902 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.00087% 14/1,608,972 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,826
European (non-Finnish)grpmax	0.0011%	90,608

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1342Trp
Coding: c.4024C>T
MANE Select: NM_001271
dbSNP: rs374407665
Type: single nucleotide variant
Location: chr15:93000527 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1342: a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance); the 'disordered' region

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.Arg1342Gln Likely benign ★★ ⚠ same residue
CHD2 p.Arg1342Leu 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
CHD2 p.Ala879Val 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-arg1342trp (accessed [today's date]).

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