Is CHAMP1 p.Pro185Ser (c.553C>T) pathogenic?

CHAMP1 p.Pro185Ser (c.553C>T) is classified Conflicting classifications of pathogenicity in CHAMP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-07). AlphaMissense: likely benign (0.0713); Ultra-rare (popmax 0.0329%, mid); Associated with complex neurodevelopmental disorder.

What condition is associated with CHAMP1 p.Pro185Ser (c.553C>T)?

CHAMP1 p.Pro185Ser (c.553C>T) is associated with complex neurodevelopmental disorder (ClinVar).

How common is CHAMP1 p.Pro185Ser (c.553C>T) in the general population?

CHAMP1 p.Pro185Ser (c.553C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHAMP1 p.Pro185Ser (c.553C>T)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

CHAMP1 p.Pro185Ser

c.553C>T · VCV3779065

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complex neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -7.85	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 0.34	GERP 0.56, phastCons 0.036
Regional constraint	o/e 1.21	unconstrained · MANE · 1,781 bp · p 1.6e-08 · regional, not allelic
Overall
CADD	18.85	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000805% 13/1,614,058 alleles · ultra-rare exomes 12/1,461,868 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000763%	131,115

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: CHAMP1
Protein: p.Pro185Ser
Coding: c.553C>T
MANE Select: NM_032436
Type: single nucleotide variant
Location: chr13:114324395 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 48.04 · 4 PDB
Residue 185: the 'disordered' region

Full CHAMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complex neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

CHAMP1 p.Arg13His Likely benign ★★ same condition
CHAMP1 p.Pro564Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
CHAMP1 p.Trp449Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
CHAMP1 p.Arg398Ter Pathogenic ★★ same type
CHAMP1 p.Arg497Ter Pathogenic ★★ same type
CHAMP1 p.Lys620Ter Pathogenic ★★ same type
CHAMP1 p.Tyr709Ter Pathogenic/Likely pathogenic ★★ same type
CHAMP1 p.Ala304Val Uncertain significance ★★ ⚠ 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/champ1-p-pro185ser (accessed [today's date]).

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