Is CHD4 p.Pro532Ser (c.1594C>T) pathogenic?

CHD4 p.Pro532Ser (c.1594C>T) is classified Uncertain significance in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-25). AlphaMissense: likely benign (0.1789); Ultra-rare (popmax 0.0329%, mid).

How common is CHD4 p.Pro532Ser (c.1594C>T) in the general population?

CHD4 p.Pro532Ser (c.1594C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CHD4 p.Pro532Ser (c.1594C>T)?

AlphaMissense predicts likely benign (score 0.1789) — an in-silico prediction, not a clinical call.

CHD4 p.Pro532Ser

c.1594C>T · rs1244201059 · VCV1690946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1789	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -10.99	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
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 0.95	unconstrained · MANE · 101 bp · p 0.72 · regional, not allelic
Overall
CADD	24.1	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000991% 16/1,614,034 alleles · ultra-rare exomes 15/1,461,818 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Admixed American	0.00167%	60,002
European (non-Finnish)	0.0011%	90,770

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.Pro532Ser
Coding: c.1594C>T
MANE Select: NM_001273
dbSNP: rs1244201059
Type: single nucleotide variant
Location: chr12:6598314 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 532: the chromo 1 domain; an α-helix; the 'disordered' region

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

Similar variants

CHD4 p.Pro532Arg Uncertain significance ★ same residue
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

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-pro532ser (accessed [today's date]).

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