Is CHD8 p.Arg2290Ser (c.6870A>C) pathogenic?

CHD8 p.Arg2290Ser (c.6870A>C) is classified Uncertain significance in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-10). AlphaMissense: ambiguous (0.3987); Very rare (popmax 0.00167%, amr).

How common is CHD8 p.Arg2290Ser (c.6870A>C) in the general population?

CHD8 p.Arg2290Ser (c.6870A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CHD8 p.Arg2290Ser (c.6870A>C)?

AlphaMissense predicts ambiguous (score 0.3987) — an in-silico prediction, not a clinical call.

CHD8 p.Arg2290Ser

c.6870A>C · rs1307750942 · VCV597884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.3987	ambiguous
REVEL	0.491	indeterminate
SaProt	LLR -7.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 6,280 bp · p 0.0041 · regional, not allelic
Overall
CADD	18.22	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 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000186% 3/1,611,734 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,368
African / African-American	0.00134%	74,864

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.Arg2290Ser
Coding: c.6870A>C
MANE Select: NM_001170629
dbSNP: rs1307750942
Type: single nucleotide variant
Location: chr14:21391848 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2290: the 'interaction with fam124b' region

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

Similar variants

CHD8 p.Arg2290Lys Uncertain significance ★ ⚠ same residue
CHD8 c.3882+1G>A Pathogenic/Likely pathogenic ★★ same type
CHD8 p.Arg1188Ter Pathogenic ★★ same type
CHD8 p.Arg1242Gln Likely pathogenic ★★ same type
CHD8 p.Arg1242Ter Pathogenic ★★ same type
CHD8 p.Arg1245Ter Pathogenic ★★ same type
CHD8 p.Arg1337Ter Pathogenic ★★ same type
CHD8 p.Arg1402Ter Pathogenic/Likely pathogenic ★★ same type

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-arg2290ser (accessed [today's date]).

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