Is CHD8 p.Phe2265= (c.6795C>T) pathogenic?

CHD8 p.Phe2265= (c.6795C>T) is classified Conflicting classifications of pathogenicity in CHD8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-09-08). Very rare (popmax 0.000763%, nfe); Associated with intellectual developmental disorder with autism and macrocephaly.

What condition is associated with CHD8 p.Phe2265= (c.6795C>T)?

CHD8 p.Phe2265= (c.6795C>T) is associated with intellectual developmental disorder with autism and macrocephaly (ClinVar).

How common is CHD8 p.Phe2265= (c.6795C>T) in the general population?

CHD8 p.Phe2265= (c.6795C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

How is CHD8 overgrowth syndrome inherited?

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

CHD8 p.Phe2265=

c.6795C>T · rs747289672 · VCV1755467

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

intellectual developmental disorder with autism and macrocephaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.5, phastCons 1
Overall
CADD	11.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,578 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,358 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.Phe2265=
Coding: c.6795C>T
MANE Select: NM_001170629
dbSNP: rs747289672
Type: single nucleotide variant
Location: chr14:21391923 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2265: the 'interaction with fam124b' 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-phe2265 (accessed [today's date]).

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