Is CHD4 p.Ser531Phe (c.1592C>T) pathogenic?

CHD4 p.Ser531Phe (c.1592C>T) is classified Likely benign in CHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely benign (0.1419); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHD4 p.Ser531Phe (c.1592C>T)?

CHD4 p.Ser531Phe (c.1592C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD4 p.Ser531Phe (c.1592C>T) in the general population?

CHD4 p.Ser531Phe (c.1592C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CHD4 p.Ser531Phe (c.1592C>T)?

AlphaMissense predicts likely benign (score 0.1419) — an in-silico prediction, not a clinical call.

CHD4 p.Ser531Phe

c.1592C>T · VCV4227785

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1419 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1419	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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	26.3	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 0.00312%

Overall 0.00291% 47/1,614,048 alleles · ultra-rare exomes 41/1,461,808 · genomes 6/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
South Asian	0.00878%	11,385
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00288%	34,706

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.Ser531Phe
Coding: c.1592C>T
MANE Select: NM_001273
Type: single nucleotide variant
Location: chr12:6598316 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 531: the chromo 1 domain; an α-helix; a modified residue (phosphoserine); the 'disordered' region

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.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
CHD4 p.Glu406Lys 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-ser531phe (accessed [today's date]).

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