Is CRPPA p.Asp333= (c.999T>C) pathogenic?

CRPPA p.Asp333= (c.999T>C) is classified Conflicting classifications of pathogenicity in CRPPA (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-12). Ultra-rare (popmax 0.0248%, nfe); Associated with Congenital Muscular Dystrophy, alpha-dystroglycan related.

How common is CRPPA p.Asp333= (c.999T>C) in the general population?

CRPPA p.Asp333= (c.999T>C) is ultra-rare (popmax 0.0248%, nfe) (gnomAD).

CRPPA p.Asp333=

Q: What condition is associated with CRPPA p.Asp333= (c.999T>C)?

CRPPA p.Asp333= (c.999T>C) is associated with Congenital Muscular Dystrophy, alpha-dystroglycan related, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, autosomal recessive limb-girdle muscular dystrophy type 2U (ClinVar).

c.999T>C · rs376909665 · VCV281957

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0248%, nfe)

Conditions

Congenital Muscular Dystrophy, alpha-dystroglycan related

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.81	GERP -5.6
Overall
CADD	0.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0248% European (non-Finnish) · 292/1,178,252 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.0202% 325/1,611,064 alleles · ultra-rare exomes 288/1,458,952 · genomes 37/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0248%	4,035
Admixed American	0.0235%	4,261
Remaining individualsnot grpmax-eligible	0.0225%	4,454
African / African-American	0.004%	24,977
South Asian	0.0022%	45,369

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: CRPPA
Protein: p.Asp333=
Coding: c.999T>C
MANE Select: NM_001101426
dbSNP: rs376909665
Type: single nucleotide variant
Location: chr7:16258947 (GRCh38)
Gene constraint: LOEUF 1.462 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.63 · 1 PDB
Residue 333: a UniProt-annotated variant site (in mddgc7; atypical form presenting with congenital muscular dystrophy)

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

Disease context

Congenital Muscular Dystrophy, alpha-dystroglycan related

Also linked: muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 autosomal recessive limb-girdle muscular dystrophy type 2U

Similar variants

CRPPA p.Asp333Glu Uncertain significance ★ ⚠ same residue
CRPPA c.1120-1G>T Pathogenic ★★ same condition
CRPPA c.258-1G>C Pathogenic/Likely pathogenic ★★ same condition
CRPPA c.835+2T>C Pathogenic/Likely pathogenic ★★ same condition
CRPPA p.Arg184Ter Pathogenic ★★ same condition
CRPPA p.Arg205Cys Likely pathogenic ★★ same condition
CRPPA p.Arg268Ter Pathogenic ★★ same condition
CRPPA p.Gln215Ter Pathogenic/Likely pathogenic ★★ 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/crppa-p-asp333 (accessed [today's date]).

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