Is CHD4 p.Arg1389Ser (c.4165C>A) pathogenic?

CHD4 p.Arg1389Ser (c.4165C>A) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-07). AlphaMissense: likely pathogenic (0.987); Absent from gnomAD v4.1; Associated with Sifrim-Hitz-Weiss syndrome.

What condition is associated with CHD4 p.Arg1389Ser (c.4165C>A)?

CHD4 p.Arg1389Ser (c.4165C>A) is associated with Sifrim-Hitz-Weiss syndrome (ClinVar).

How common is CHD4 p.Arg1389Ser (c.4165C>A) in the general population?

CHD4 p.Arg1389Ser (c.4165C>A) is absent from gnomAD v4.1 (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.Arg1389Ser (c.4165C>A)?

AlphaMissense predicts likely pathogenic (score 0.987) — an in-silico prediction, not a clinical call.

CHD4 p.Arg1389Ser

c.4165C>A · rs2540382709 · VCV2691876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sifrim-Hitz-Weiss syndrome

Computational evidence

Protein change
AlphaMissense	0.987	likely pathogenic
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 461 bp · p 1.9e-05 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHD4
Protein: p.Arg1389Ser
Coding: c.4165C>A
MANE Select: NM_001273
dbSNP: rs2540382709
Type: single nucleotide variant
Location: chr12:6582919 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 1389: 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.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-arg1389ser (accessed [today's date]).

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