Is CHD4 p.Ala1522Pro (c.4564G>C) pathogenic?

CHD4 p.Ala1522Pro (c.4564G>C) is classified Uncertain significance in CHD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.889); Absent from gnomAD v4.1.

How common is CHD4 p.Ala1522Pro (c.4564G>C) in the general population?

CHD4 p.Ala1522Pro (c.4564G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHD4 p.Ala1522Pro (c.4564G>C)?

AlphaMissense predicts likely pathogenic (score 0.889) — an in-silico prediction, not a clinical call.

CHD4 p.Ala1522Pro

c.4564G>C · rs776080022 · VCV1378497

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.889 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.889	likely pathogenic
REVEL	0.561	indeterminate
SaProt	LLR -4.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.9, phastCons 0.93
Regional constraint	o/e 1.00	unconstrained · MANE · 3,351 bp · p 0.98 · regional, not allelic
Overall
CADD	27.0	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.Ala1522Pro
Coding: c.4564G>C
MANE Select: NM_001273
dbSNP: rs776080022
Type: single nucleotide variant
Location: chr12:6581766 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB

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

Similar variants

CHD4 p.Arg1068His Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1173Gln Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1173Trp Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1177Cys Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1177His Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1183Cys Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1183His Pathogenic/Likely pathogenic ★★ same type
CHD4 p.Arg1340Cys Pathogenic ★★ same type

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-ala1522pro (accessed [today's date]).

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