Is CHD4 p.Arg102Cys (c.304C>T) pathogenic?

CHD4 p.Arg102Cys (c.304C>T) is classified Conflicting classifications of pathogenicity in CHD4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.1458); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHD4 p.Arg102Cys (c.304C>T)?

CHD4 p.Arg102Cys (c.304C>T) is associated with Inborn genetic diseases, Sifrim-Hitz-Weiss syndrome (ClinVar).

How common is CHD4 p.Arg102Cys (c.304C>T) in the general population?

CHD4 p.Arg102Cys (c.304C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CHD4 p.Arg102Cys (c.304C>T)?

AlphaMissense predicts likely benign (score 0.1458) — an in-silico prediction, not a clinical call.

CHD4 p.Arg102Cys

c.304C>T · rs138116135 · VCV2439986

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1458 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1458	likely benign
REVEL	0.654	pathogenic-leaning
SaProt	LLR -6.66	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 4,403 bp · p 0.0078 · regional, not allelic
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.0026% 42/1,613,366 alleles · ultra-rare exomes 35/1,461,638 · genomes 7/151,728 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.0133%	7,494
Remaining individualsnot grpmax-eligible	0.00801%	12,491
South Asian	0.00549%	18,213
European (non-Finnish)	0.00195%	51,299

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: CHD4
Protein: p.Arg102Cys
Coding: c.304C>T
MANE Select: NM_001273
dbSNP: rs138116135
Type: single nucleotide variant
Location: chr12:6602094 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 102: the 'disordered' region

Full CHD4 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: Sifrim-Hitz-Weiss syndrome

Similar variants

CHD4 p.Arg1068His Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1173Gln Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1173Trp Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1177Cys Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1183Cys Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1183His Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1340Cys Pathogenic ★★ same condition
CHD4 p.Arg887Gln 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/chd4-p-arg102cys (accessed [today's date]).

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