Is CHD8 p.Ser491= (c.1473C>T) pathogenic?

CHD8 p.Ser491= (c.1473C>T) is classified Likely benign in CHD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Ser491= (c.1473C>T)?

CHD8 p.Ser491= (c.1473C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD8 p.Ser491= (c.1473C>T) in the general population?

CHD8 p.Ser491= (c.1473C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

CHD8 p.Ser491=

c.1473C>T · rs373467208 · VCV705907

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.85	GERP -5.6
Overall
CADD	6.733	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/75,050 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00235% 38/1,614,024 alleles · ultra-rare exomes 24/1,461,712 · genomes 14/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,169
Remaining individualsnot grpmax-eligible	0.016%	6,249
Admixed American	0.015%	6,669
European (non-Finnish)	8.48e-05%	1,179,889

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.Ser491=
Coding: c.1473C>T
MANE Select: NM_001170629
dbSNP: rs373467208
Type: single nucleotide variant
Location: chr14:21427997 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 491: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD8 c.3882+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg1462Ter Pathogenic ★★ same condition
CHD8 p.Arg1582Ter Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg2217Ter Pathogenic ★★ same condition
CHD8 p.Arg243Ter Pathogenic ★★ same condition
CHD8 c.4921+4C>T Uncertain significance ★★ same condition
CHD8 c.-1G>A Uncertain significance ★★ same condition
CHD8 p.Ala1960Thr 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-ser491 (accessed [today's date]).

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