Is CHD8 p.Pro134Ser (c.400C>T) pathogenic?

CHD8 p.Pro134Ser (c.400C>T) is classified Conflicting classifications of pathogenicity in CHD8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.7283); Very rare (popmax 0.00636%, nfe).

How common is CHD8 p.Pro134Ser (c.400C>T) in the general population?

CHD8 p.Pro134Ser (c.400C>T) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about CHD8 p.Pro134Ser (c.400C>T)?

AlphaMissense predicts likely pathogenic (score 0.7283) — an in-silico prediction, not a clinical call.

CHD8 p.Pro134Ser

c.400C>T · rs763843295 · VCV1700804

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7283 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7283	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 808 bp · p 0.19 · regional, not allelic
Overall
CADD	23.7	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 0.00636% European (non-Finnish) · 75/1,178,998 alleles

Filtering AF 0.0052% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00482% 77/1,597,490 alleles · very rare exomes 74/1,445,252 · genomes 3/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,720
African / African-American	0.00267%	37,446

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.Pro134Ser
Coding: c.400C>T
MANE Select: NM_001170629
dbSNP: rs763843295
Type: single nucleotide variant
Location: chr14:21431244 (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

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-pro134ser (accessed [today's date]).

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