Is CHD2 p.Arg1345Pro (c.4034G>C) pathogenic?

CHD2 p.Arg1345Pro (c.4034G>C) is classified Likely benign in CHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-23). AlphaMissense: likely pathogenic (0.7258); Ultra-rare (popmax 0.0101%, amr); Associated with developmental and epileptic encephalopathy 94.

What condition is associated with CHD2 p.Arg1345Pro (c.4034G>C)?

CHD2 p.Arg1345Pro (c.4034G>C) is associated with developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Arg1345Pro (c.4034G>C) in the general population?

CHD2 p.Arg1345Pro (c.4034G>C) is ultra-rare (popmax 0.0101%, amr) (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.Arg1345Pro (c.4034G>C)?

AlphaMissense predicts likely pathogenic (score 0.7258) — an in-silico prediction, not a clinical call.

CHD2 p.Arg1345Pro

c.4034G>C · rs751507887 · VCV507397

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy 94

Computational evidence

Protein change
AlphaMissense	0.7258	likely pathogenic
REVEL	0.441	indeterminate
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.68 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,067 bp · p 0.73 · regional, not allelic
Overall
CADD	28.9	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 0.0101% Admixed American · 6/59,574 alleles

Filtering AF 0.00431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00297%

Overall 0.00118% 19/1,611,386 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,929
Remaining individualsnot grpmax-eligible	0.00321%	31,165
European (non-Finnish)	0.000933%	107,157

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.Arg1345Pro
Coding: c.4034G>C
MANE Select: NM_001271
dbSNP: rs751507887
Type: single nucleotide variant
Location: chr15:93000537 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1345: 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.Arg1345Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CHD2 p.Arg1345Trp Uncertain significance ★ ⚠ same residue
CHD2 p.Arg1345= Likely benign ★ 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-arg1345pro (accessed [today's date]).

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