Is CHD8 p.Pro755Ser (c.2263C>T) pathogenic?

CHD8 p.Pro755Ser (c.2263C>T) is classified Uncertain significance in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-11). AlphaMissense: likely pathogenic (0.8556); Very rare (popmax 8.48e-05%, nfe); Associated with intellectual developmental disorder with autism and macrocephaly.

What condition is associated with CHD8 p.Pro755Ser (c.2263C>T)?

CHD8 p.Pro755Ser (c.2263C>T) is associated with intellectual developmental disorder with autism and macrocephaly (ClinVar).

How common is CHD8 p.Pro755Ser (c.2263C>T) in the general population?

CHD8 p.Pro755Ser (c.2263C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is CHD8 overgrowth syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHD8 p.Pro755Ser (c.2263C>T)?

AlphaMissense predicts likely pathogenic (score 0.8556) — an in-silico prediction, not a clinical call.

CHD8 p.Pro755Ser

c.2263C>T · rs2501930195 · VCV2440007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder with autism and macrocephaly

Computational evidence

Protein change
AlphaMissense	0.8556	likely pathogenic
REVEL	0.457	indeterminate
SaProt	LLR -6.99	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 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 9,080 bp · p 5.6e-32 · regional, not allelic
Overall
CADD	25.3	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 8.48e-05% European (non-Finnish) · 1/1,179,398 alleles

Overall 6.84e-05% 1/1,461,028 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: CHD8
Protein: p.Pro755Ser
Coding: c.2263C>T
MANE Select: NM_001170629
dbSNP: rs2501930195
Type: single nucleotide variant
Location: chr14:21409952 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 755: the chromo 2 domain

Full CHD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with autism and macrocephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CHD8 overgrowth syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

CHD8 c.3882+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg1188Ter Pathogenic ★★ same condition
CHD8 p.Arg1242Gln Likely pathogenic ★★ same condition
CHD8 p.Arg1242Ter Pathogenic ★★ same condition
CHD8 p.Arg1337Ter Pathogenic ★★ same condition
CHD8 p.Arg1402Ter Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg1460Ter Pathogenic ★★ same condition
CHD8 p.Arg1462Ter Pathogenic ★★ 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/chd8-p-pro755ser (accessed [today's date]).

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