Is CHD2 p.Arg199Cys (c.595C>T) pathogenic?

CHD2 p.Arg199Cys (c.595C>T) is classified Conflicting classifications of pathogenicity in CHD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-09). AlphaMissense: likely benign (0.2361); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHD2 p.Arg199Cys (c.595C>T)?

CHD2 p.Arg199Cys (c.595C>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Arg199Cys (c.595C>T) in the general population?

CHD2 p.Arg199Cys (c.595C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CHD2 p.Arg199Cys (c.595C>T)?

AlphaMissense predicts likely benign (score 0.2361) — an in-silico prediction, not a clinical call.

CHD2 p.Arg199Cys

c.595C>T · rs764705223 · VCV943841

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2361 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2361	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -11.74	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 11 kb · p 0.18 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00123% 18/1,461,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.0022%	45,535
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	0.0011%	90,769

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.Arg199Cys
Coding: c.595C>T
MANE Select: NM_001271
dbSNP: rs764705223
Type: single nucleotide variant
Location: chr15:92939621 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 199: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy 94

Similar variants

CHD2 p.Arg199Pro Likely benign ★★ ⚠ same residue
CHD2 p.Arg199His Conflicting classifications of pathogenicity ★ ⚠ same residue
CHD2 p.Arg199Ser 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-arg199cys (accessed [today's date]).

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