Is CHD8 p.Asp7Glu (c.21T>G) pathogenic?

CHD8 p.Asp7Glu (c.21T>G) is classified Uncertain significance in CHD8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.8578); Very rare (popmax 0.00174%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Asp7Glu (c.21T>G)?

CHD8 p.Asp7Glu (c.21T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHD8 p.Asp7Glu (c.21T>G) in the general population?

CHD8 p.Asp7Glu (c.21T>G) is very rare (popmax 0.00174%, nfe) (gnomAD).

What do computational predictors say about CHD8 p.Asp7Glu (c.21T>G)?

AlphaMissense predicts likely pathogenic (score 0.8578) — an in-silico prediction, not a clinical call.

CHD8 p.Asp7Glu

c.21T>G · rs769940681 · VCV1308409

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8578 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00174%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8578	likely pathogenic
REVEL	0.195	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.23, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 808 bp · p 0.19 · regional, not allelic
Overall
CADD	20.7	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 0.00174% European (non-Finnish) · 20/1,147,308 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000925%

Overall 0.0013% 20/1,539,428 alleles · very rare

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.Asp7Glu
Coding: c.21T>G
MANE Select: NM_001170629
dbSNP: rs769940681
Type: single nucleotide variant
Location: chr14:21431623 (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

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-asp7glu (accessed [today's date]).

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