Is CHD4 p.Arg75Cys (c.223C>T) pathogenic?

CHD4 p.Arg75Cys (c.223C>T) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.292); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CHD4 p.Arg75Cys (c.223C>T)?

CHD4 p.Arg75Cys (c.223C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD4 p.Arg75Cys (c.223C>T) in the general population?

CHD4 p.Arg75Cys (c.223C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CHD4 p.Arg75Cys (c.223C>T)?

AlphaMissense predicts likely benign (score 0.292) — an in-silico prediction, not a clinical call.

CHD4 p.Arg75Cys

c.223C>T · rs749142192 · VCV2244627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.292	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	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 0.00223% East Asian · 1/44,862 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,778 alleles · very rare exomes 5/1,461,658 · genomes 0/152,120 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
European (non-Finnish)	0.000339%	294,976

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.Arg75Cys
Coding: c.223C>T
MANE Select: NM_001273
dbSNP: rs749142192
Type: single nucleotide variant
Location: chr12:6602175 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 75: 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

Similar variants

CHD4 p.Arg75His Conflicting classifications of pathogenicity ★ ⚠ same residue
CHD4 p.Arg1173Gln Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Ala1718Val Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg1288Trp Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg611His Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg836Cys Uncertain significance ★★ ⚠ same condition
CHD4 p.Asp1395Glu Uncertain significance ★★ ⚠ same condition
CHD4 p.Asp1659Gly Uncertain significance ★★ ⚠ 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-arg75cys (accessed [today's date]).

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