What condition is associated with CHD4 p.Pro8Ser (c.22C>T)?

CHD4 p.Pro8Ser (c.22C>T) is associated with Moyamoya angiopathy with developmental delay (ClinVar).

How common is CHD4 p.Pro8Ser (c.22C>T) in the general population?

CHD4 p.Pro8Ser (c.22C>T) is very rare (popmax 8.61e-05%, nfe) (gnomAD).

What do computational predictors say about CHD4 p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

CHD4 p.Pro8Ser

Q: Is CHD4 p.Pro8Ser (c.22C>T) pathogenic?

CHD4 p.Pro8Ser (c.22C>T) is classified Likely pathogenic in CHD4 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.0879); Very rare (popmax 8.61e-05%, nfe); Associated with Moyamoya angiopathy with developmental delay.

c.22C>T · rs1948698590 · VCV982178

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.61e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Moyamoya angiopathy with developmental delay

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign ⚠ discordant with ClinVar
REVEL	0.294	indeterminate
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.91, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 4,403 bp · p 0.0078 · regional, not allelic
Overall
CADD	25.8	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 8.61e-05% European (non-Finnish) · 1/1,162,106 alleles

Overall 7.05e-05% 1/1,419,086 alleles · very rare

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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_001273
dbSNP: rs1948698590
Type: single nucleotide variant
Location: chr12:6606352 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 8: the 'disordered' region

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

Disease context

Moyamoya angiopathy with developmental delay

Similar variants

CHD4 p.Pro8Leu Uncertain significance ★ ⚠ same residue
CHD4 p.Glu536Val Uncertain significance ★★ ⚠ same condition
CHD4 p.Thr709Ala Uncertain significance ★★ ⚠ same condition
CHD4 p.Arg1068Ser Likely pathogenic ★ same condition
CHD4 p.Arg877Gln Likely pathogenic ★ same condition
CHD4 p.Cys376Ter Likely pathogenic ★ same condition
CHD4 p.Met1210Thr Likely pathogenic ★ ⚠ same condition
CHD4 p.Ala1601Ser Conflicting classifications of pathogenicity ★ ⚠ 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-pro8ser (accessed [today's date]).

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