Is CHD4 p.Pro29Arg (c.86C>G) pathogenic?

CHD4 p.Pro29Arg (c.86C>G) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-27). AlphaMissense: likely benign (0.1106); Very rare (popmax 8.6e-05%, nfe); Associated with Sifrim-Hitz-Weiss syndrome.

What condition is associated with CHD4 p.Pro29Arg (c.86C>G)?

CHD4 p.Pro29Arg (c.86C>G) is associated with Sifrim-Hitz-Weiss syndrome (ClinVar).

How common is CHD4 p.Pro29Arg (c.86C>G) in the general population?

CHD4 p.Pro29Arg (c.86C>G) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

How is CHD4-related neurodevelopmental disorder inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHD4 p.Pro29Arg (c.86C>G)?

AlphaMissense predicts likely benign (score 0.1106) — an in-silico prediction, not a clinical call.

CHD4 p.Pro29Arg

c.86C>G · VCV4846992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sifrim-Hitz-Weiss syndrome

Computational evidence

Protein change
AlphaMissense	0.1106	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -8.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.96, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 4,403 bp · p 0.0078 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.6e-05% European (non-Finnish) · 1/1,163,094 alleles

Overall 7.01e-05% 1/1,426,148 alleles · very rare

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.Pro29Arg
Coding: c.86C>G
MANE Select: NM_001273
Type: single nucleotide variant
Location: chr12:6606288 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 29: the 'disordered' region

Full CHD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Sifrim-Hitz-Weiss syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CHD4-related neurodevelopmental disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

CHD4 p.Pro29= Benign/Likely benign ★★ same residue
CHD4 p.Pro29Ser Likely benign same residue
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

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-pro29arg (accessed [today's date]).

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