Is CHD8 p.Val604Ala (c.1811T>C) pathogenic?

CHD8 p.Val604Ala (c.1811T>C) is classified Uncertain significance in CHD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.9294); Very rare (popmax 0.000424%, nfe); Associated with intellectual developmental disorder with autism and macrocephaly.

What condition is associated with CHD8 p.Val604Ala (c.1811T>C)?

CHD8 p.Val604Ala (c.1811T>C) is associated with intellectual developmental disorder with autism and macrocephaly (ClinVar).

How common is CHD8 p.Val604Ala (c.1811T>C) in the general population?

CHD8 p.Val604Ala (c.1811T>C) is very rare (popmax 0.000424%, 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.Val604Ala (c.1811T>C)?

AlphaMissense predicts likely pathogenic (score 0.9294) — an in-silico prediction, not a clinical call.

CHD8 p.Val604Ala

c.1811T>C · rs1485668022 · VCV1780600

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with autism and macrocephaly

Computational evidence

Protein change
AlphaMissense	0.9294	likely pathogenic
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 12 kb · p 0.00038 · regional, not allelic
Overall
CADD	20.7	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 0.000424% European (non-Finnish) · 5/1,179,834 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,818 alleles · very rare exomes 4/1,461,650 · genomes 1/152,168 · joint denominator

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.Val604Ala
Coding: c.1811T>C
MANE Select: NM_001170629
dbSNP: rs1485668022
Type: single nucleotide variant
Location: chr14:21415813 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 604: the 'disordered' region

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-val604ala (accessed [today's date]).

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