Is CHD8 p.Val1159= (c.3477G>A) pathogenic?

CHD8 p.Val1159= (c.3477G>A) is classified Benign in CHD8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 94.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Val1159= (c.3477G>A)?

CHD8 p.Val1159= (c.3477G>A) is associated with Inborn genetic diseases (ClinVar).

CHD8 p.Val1159=

Q: How common is CHD8 p.Val1159= (c.3477G>A) in the general population?

CHD8 p.Val1159= (c.3477G>A) is common (popmax 94.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3477G>A · rs8022395 · VCV587786

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 94.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.026	moderately benign-leaning
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.2	GERP -2.9, phastCons 1
Overall
CADD	12.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 94.5% African / African-American · 70,873/75,014 alleles

Filtering AF 93.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 93.7%

Overall 92.7% 1,495,298/1,613,230 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	96.2%	1
Amishnot grpmax-eligible	95.9%	1
African / African-Americangrpmax	94.5%	1
European (non-Finnish)	93.5%	1
Middle Eastern	93.3%	1
Remaining individualsnot grpmax-eligible	93%	1
South Asian	91.8%	1
East Asian	89.4%	1
Finnishnot grpmax-eligible	89.1%	1
Admixed American	79.3%	1

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val1159=
Coding: c.3477G>A
MANE Select: NM_001170629
dbSNP: rs8022395
Type: single nucleotide variant
Location: chr14:21403494 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 1159: the helicase c-terminal domain

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-val1159 (accessed [today's date]).

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