Is CHD8 p.Pro68Ser (c.202C>T) pathogenic?

CHD8 p.Pro68Ser (c.202C>T) is classified Uncertain significance in CHD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-15). AlphaMissense: likely benign (0.0661); Very rare (popmax 0.00724%, nfe).

How common is CHD8 p.Pro68Ser (c.202C>T) in the general population?

CHD8 p.Pro68Ser (c.202C>T) is very rare (popmax 0.00724%, nfe) (gnomAD).

What do computational predictors say about CHD8 p.Pro68Ser (c.202C>T)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

CHD8 p.Pro68Ser

c.202C>T · rs1049466654 · VCV1722977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00724%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.37	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 1.8	GERP -0.86, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 808 bp · p 0.19 · regional, not allelic
Overall
CADD	18.22	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 0.00724% European (non-Finnish) · 83/1,146,900 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00548%

Overall 0.00573% 88/1,537,076 alleles · very rare exomes 85/1,384,928 · genomes 3/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00724%	13,818
Remaining individualsnot grpmax-eligible	0.00667%	15,002
African / African-American	0.00137%	73,022

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.Pro68Ser
Coding: c.202C>T
MANE Select: NM_001170629
dbSNP: rs1049466654
Type: single nucleotide variant
Location: chr14:21431442 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 68: the 'disordered' region

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

Similar variants

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
CHD8 p.Arg1402Ter Pathogenic/Likely pathogenic ★★ same type
CHD8 p.Arg1460Ter 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-pro68ser (accessed [today's date]).

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