Is CHD4 p.Arg684Pro (c.2051G>C) pathogenic?

CHD4 p.Arg684Pro (c.2051G>C) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-12). AlphaMissense: likely pathogenic (0.9559); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CHD4 p.Arg684Pro (c.2051G>C)?

CHD4 p.Arg684Pro (c.2051G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CHD4 p.Arg684Pro (c.2051G>C) in the general population?

CHD4 p.Arg684Pro (c.2051G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHD4 p.Arg684Pro (c.2051G>C)?

AlphaMissense predicts likely pathogenic (score 0.9559) — an in-silico prediction, not a clinical call.

CHD4 p.Arg684Pro

c.2051G>C · VCV4868890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9559 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9559	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -4.16	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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 3,432 bp · p 2e-05 · regional, not allelic
Overall
CADD	25.5	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.Arg684Pro
Coding: c.2051G>C
MANE Select: NM_001273
Type: single nucleotide variant
Location: chr12:6595404 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 684: the chromo 2 domain

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.Arg684Ter Uncertain significance ★ 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-arg684pro (accessed [today's date]).

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