Is CHD8 p.Arg2420Ser (c.7258C>A) pathogenic?

CHD8 p.Arg2420Ser (c.7258C>A) is classified Uncertain significance in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-07). AlphaMissense: likely benign (0.3219); Very rare (popmax 0.00193%, amr).

How common is CHD8 p.Arg2420Ser (c.7258C>A) in the general population?

CHD8 p.Arg2420Ser (c.7258C>A) is very rare (popmax 0.00193%, amr) (gnomAD).

What do computational predictors say about CHD8 p.Arg2420Ser (c.7258C>A)?

AlphaMissense predicts likely benign (score 0.3219) — an in-silico prediction, not a clinical call.

CHD8 p.Arg2420Ser

c.7258C>A · VCV3368804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00193%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3219	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 6,280 bp · p 0.0041 · regional, not allelic
Overall
CADD	22.4	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 0.00193% Admixed American · 1/51,772 alleles

Overall 6.41e-05% 1/1,559,240 alleles · very rare exomes 1/1,406,986 · genomes 0/152,254 · 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.Arg2420Ser
Coding: c.7258C>A
MANE Select: NM_001170629
Type: single nucleotide variant
Location: chr14:21386101 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB

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

Similar variants

CHD8 p.Arg2420Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHD8 p.Arg2420His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg2420ser (accessed [today's date]).

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