Is CHD4 p.Val454Phe (c.1360G>T) pathogenic?

CHD4 p.Val454Phe (c.1360G>T) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.929); Absent from gnomAD v4.1; Associated with Sifrim-Hitz-Weiss syndrome.

What condition is associated with CHD4 p.Val454Phe (c.1360G>T)?

CHD4 p.Val454Phe (c.1360G>T) is associated with Sifrim-Hitz-Weiss syndrome (ClinVar).

How common is CHD4 p.Val454Phe (c.1360G>T) in the general population?

CHD4 p.Val454Phe (c.1360G>T) 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.Val454Phe (c.1360G>T)?

AlphaMissense predicts likely pathogenic (score 0.929) — an in-silico prediction, not a clinical call.

CHD4 p.Val454Phe

c.1360G>T · VCV4854066

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.929 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sifrim-Hitz-Weiss syndrome

Computational evidence

Protein change
AlphaMissense	0.929	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -12.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.77, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 1,544 bp · p 2.4e-08 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Val454Phe
Coding: c.1360G>T
MANE Select: NM_001273
Type: single nucleotide variant
Location: chr12:6599895 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 454: a turn

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.Val454= 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
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-val454phe (accessed [today's date]).

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