Is CHD8 p.Ser525Pro (c.1573T>C) pathogenic?

CHD8 p.Ser525Pro (c.1573T>C) is classified Benign/Likely benign in CHD8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.1378); Rare (popmax 0.312%, sas); Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Ser525Pro (c.1573T>C)?

CHD8 p.Ser525Pro (c.1573T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CHD8 p.Ser525Pro (c.1573T>C) in the general population?

CHD8 p.Ser525Pro (c.1573T>C) is rare (popmax 0.312%, sas) (gnomAD).

What do computational predictors say about CHD8 p.Ser525Pro (c.1573T>C)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

CHD8 p.Ser525Pro

c.1573T>C · rs771409666 · VCV588653

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.312%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -7.03	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 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 12 kb · p 0.00038 · regional, not allelic
Overall
CADD	22.4	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 0.312% South Asian · 284/91,090 alleles

Filtering AF 0.282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.0184% 297/1,613,852 alleles · rare exomes 290/1,461,662 · genomes 7/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.312%	321
Remaining individualsnot grpmax-eligible	0.0192%	5,205
Middle Eastern	0.0164%	6,082

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.Ser525Pro
Coding: c.1573T>C
MANE Select: NM_001170629
dbSNP: rs771409666
Type: single nucleotide variant
Location: chr14:21427897 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 525: 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.Ser525Ala Uncertain significance ★★ ⚠ same residue
CHD8 p.Ser525Cys Uncertain significance ★ ⚠ 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

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-ser525pro (accessed [today's date]).

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