Is CHD8 p.Ser2071Pro (c.6211T>C) pathogenic?

CHD8 p.Ser2071Pro (c.6211T>C) is classified Uncertain significance in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely pathogenic (0.6603); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with autism and macrocephaly.

What condition is associated with CHD8 p.Ser2071Pro (c.6211T>C)?

CHD8 p.Ser2071Pro (c.6211T>C) is associated with intellectual developmental disorder with autism and macrocephaly (ClinVar).

How common is CHD8 p.Ser2071Pro (c.6211T>C) in the general population?

CHD8 p.Ser2071Pro (c.6211T>C) is absent from gnomAD v4.1 (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.Ser2071Pro (c.6211T>C)?

AlphaMissense predicts likely pathogenic (score 0.6603) — an in-silico prediction, not a clinical call.

CHD8 p.Ser2071Pro

c.6211T>C · VCV4078274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6603 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder with autism and macrocephaly

Computational evidence

Protein change
AlphaMissense	0.6603	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -6.92	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 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,499 bp · p 8e-07 · regional, not allelic
Overall
CADD	23.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHD8
Protein: p.Ser2071Pro
Coding: c.6211T>C
MANE Select: NM_001170629
Type: single nucleotide variant
Location: chr14:21393584 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2071: the 'interaction with fam124b' region; the 'disordered' region; a modified residue (phosphoserine)

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-ser2071pro (accessed [today's date]).

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