Is CHD8 p.Pro1975Leu (c.5924C>T) pathogenic?

CHD8 p.Pro1975Leu (c.5924C>T) is classified Uncertain significance in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely benign (0.1227); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with autism and macrocephaly.

What condition is associated with CHD8 p.Pro1975Leu (c.5924C>T)?

CHD8 p.Pro1975Leu (c.5924C>T) is associated with intellectual developmental disorder with autism and macrocephaly (ClinVar).

How common is CHD8 p.Pro1975Leu (c.5924C>T) in the general population?

CHD8 p.Pro1975Leu (c.5924C>T) 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.Pro1975Leu (c.5924C>T)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

CHD8 p.Pro1975Leu

c.5924C>T · rs2501857149 · VCV3064946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with autism and macrocephaly

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,499 bp · p 8e-07 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Pro1975Leu
Coding: c.5924C>T
MANE Select: NM_001170629
dbSNP: rs2501857149
Type: single nucleotide variant
Location: chr14:21393871 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 1975: 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-pro1975leu (accessed [today's date]).

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