Is CHD8 p.Pro2004Ser (c.6010C>T) pathogenic?

CHD8 p.Pro2004Ser (c.6010C>T) is classified Uncertain significance in CHD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-24). AlphaMissense: likely benign (0.0766); Very rare (popmax 0.00017%, nfe); Associated with CHD8-related disorder.

What condition is associated with CHD8 p.Pro2004Ser (c.6010C>T)?

CHD8 p.Pro2004Ser (c.6010C>T) is associated with CHD8-related disorder (ClinVar).

How common is CHD8 p.Pro2004Ser (c.6010C>T) in the general population?

CHD8 p.Pro2004Ser (c.6010C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CHD8 p.Pro2004Ser (c.6010C>T)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

CHD8 p.Pro2004Ser

c.6010C>T · rs2501856752 · VCV2636660

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHD8-related disorder

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -6.31	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 3.5	GERP -0.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,499 bp · p 8e-07 · regional, not allelic
Overall
CADD	16.66	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,878 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,978 alleles · very rare exomes 2/1,461,648 · genomes 0/152,330 · 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.Pro2004Ser
Coding: c.6010C>T
MANE Select: NM_001170629
dbSNP: rs2501856752
Type: single nucleotide variant
Location: chr14:21393785 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2004: the 'interaction with fam124b' region; the 'disordered' region

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

Disease context

CHD8-related disorder

Similar variants

CHD8 p.Pro2004His Uncertain significance ★ ⚠ same residue
CHD8 p.Arg1472Ter Pathogenic ★★ same condition
CHD8 p.Arg1776Ter Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg564Ter Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Ala1076Ser Uncertain significance ★★ ⚠ same condition
CHD8 p.Arg2150Ser Uncertain significance ★★ ⚠ same condition
CHD8 p.Cys1691Tyr Uncertain significance ★★ same condition
CHD8 p.Lys520Glu Uncertain significance ★★ ⚠ 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-pro2004ser (accessed [today's date]).

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