Is CHD4 p.Pro1880Ser (c.5638C>T) pathogenic?

CHD4 p.Pro1880Ser (c.5638C>T) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-02-02). AlphaMissense: likely pathogenic (0.8931); Very rare (popmax 0.000339%, nfe); Associated with Sifrim-Hitz-Weiss syndrome.

What condition is associated with CHD4 p.Pro1880Ser (c.5638C>T)?

CHD4 p.Pro1880Ser (c.5638C>T) is associated with Sifrim-Hitz-Weiss syndrome (ClinVar).

How common is CHD4 p.Pro1880Ser (c.5638C>T) in the general population?

CHD4 p.Pro1880Ser (c.5638C>T) is very rare (popmax 0.000339%, 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.Pro1880Ser (c.5638C>T)?

AlphaMissense predicts likely pathogenic (score 0.8931) — an in-silico prediction, not a clinical call.

CHD4 p.Pro1880Ser

c.5638C>T · rs1947956104 · VCV982183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sifrim-Hitz-Weiss syndrome

Computational evidence

Protein change
AlphaMissense	0.8931	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -5.94	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 7,767 bp · p 1.8e-18 · regional, not allelic
Overall
CADD	26.9	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 0.000339% European (non-Finnish) · 4/1,180,020 alleles

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

Overall 0.000248% 4/1,614,016 alleles · very rare exomes 3/1,461,892 · genomes 1/152,124 · joint denominator

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.Pro1880Ser
Coding: c.5638C>T
MANE Select: NM_001273
dbSNP: rs1947956104
Type: single nucleotide variant
Location: chr12:6570952 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 1880: the 'required for interaction with pcnt' 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.Pro1880Leu Uncertain significance ★ ⚠ 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
CHD4 p.Arg1340Cys 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-pro1880ser (accessed [today's date]).

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