Is CHD8 p.Pro2193Ser (c.6577C>T) pathogenic?

CHD8 p.Pro2193Ser (c.6577C>T) is classified Uncertain significance in CHD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0766); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Pro2193Ser (c.6577C>T)?

CHD8 p.Pro2193Ser (c.6577C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD8 p.Pro2193Ser (c.6577C>T) in the general population?

CHD8 p.Pro2193Ser (c.6577C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CHD8 p.Pro2193Ser (c.6577C>T)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

CHD8 p.Pro2193Ser

c.6577C>T · VCV3620682

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,499 bp · p 8e-07 · regional, not allelic
Overall
CADD	17.29	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,613,972 alleles · very rare exomes 2/1,461,706 · genomes 1/152,266 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
European (non-Finnish)	8.48e-05%	1,179,901

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.Pro2193Ser
Coding: c.6577C>T
MANE Select: NM_001170629
Type: single nucleotide variant
Location: chr14:21392701 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2193: the 'interaction with fam124b' region; 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 p.Pro2193= Likely benign ★ same residue
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

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-pro2193ser (accessed [today's date]).

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