Is CHAMP1 p.Pro417Arg (c.1250C>G) pathogenic?

CHAMP1 p.Pro417Arg (c.1250C>G) is classified Conflicting classifications of pathogenicity in CHAMP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-07). AlphaMissense: likely benign (0.1932); Very rare (popmax 0.00833%, amr).

How common is CHAMP1 p.Pro417Arg (c.1250C>G) in the general population?

CHAMP1 p.Pro417Arg (c.1250C>G) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about CHAMP1 p.Pro417Arg (c.1250C>G)?

AlphaMissense predicts likely benign (score 0.1932) — an in-silico prediction, not a clinical call.

CHAMP1 p.Pro417Arg

c.1250C>G · rs1242502104 · VCV1380212

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1932	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.73, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 1,781 bp · p 1.6e-08 · regional, not allelic
Overall
CADD	22.7	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 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000558% 9/1,614,018 alleles · very rare exomes 6/1,461,894 · genomes 3/152,124 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
European (non-Finnish)	0.000339%	295,012

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.Pro417Arg
Coding: c.1250C>G
MANE Select: NM_032436
dbSNP: rs1242502104
Type: single nucleotide variant
Location: chr13:114325092 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 48.04 · 4 PDB
Residue 417: the 'disordered' region; the 'mediates interaction with mad2l2' region

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

Similar variants

CHAMP1 p.Pro417Ala Uncertain significance ★ ⚠ same residue
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
CHAMP1 p.Glu195Gly Uncertain significance ★★ ⚠ same type
CHAMP1 p.Glu524Gly 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-pro417arg (accessed [today's date]).

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