Is CHD2 p.Arg1116Cys (c.3346C>T) pathogenic?

CHD2 p.Arg1116Cys (c.3346C>T) is classified Conflicting classifications of pathogenicity in CHD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.8875); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHD2 p.Arg1116Cys (c.3346C>T)?

CHD2 p.Arg1116Cys (c.3346C>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Arg1116Cys (c.3346C>T) in the general population?

CHD2 p.Arg1116Cys (c.3346C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CHD2 p.Arg1116Cys (c.3346C>T)?

AlphaMissense predicts likely pathogenic (score 0.8875) — an in-silico prediction, not a clinical call.

CHD2 p.Arg1116Cys

c.3346C>T · rs200013427 · VCV847777

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8875	likely pathogenic
REVEL	0.464	indeterminate
SaProt	LLR -12.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.18, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 6,370 bp · p 7.8e-14 · 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

Grpmax group 0.00133% African / African-American · 1/74,916 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000929% 15/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00783%	12,772
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-Americangrpmax	0.00133%	74,916
South Asian	0.0011%	91,082
European (non-Finnish)	0.000593%	168,573

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.Arg1116Cys
Coding: c.3346C>T
MANE Select: NM_001271
dbSNP: rs200013427
Type: single nucleotide variant
Location: chr15:92985606 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1116: 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 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-arg1116cys (accessed [today's date]).

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