CRPPA

Chr 7AR

CDP-L-ribitol pyrophosphorylase A

Also known as: ISPD, LGMDR20, MDDGA7, MDDGC7, Nip, hISPD

NCBI Gene: 729920 ENSG00000214960 UniProt: A4D126 OMIM: 614631

This gene encodes a cytidylyltransferase that catalyzes the formation of CDP-ribitol, which is essential for protein O-linked mannosylation and proper functioning of alpha-dystroglycan in binding extracellular matrix proteins. Mutations cause muscular dystrophy-dystroglycanopathy with either severe congenital presentation including brain and eye anomalies (Walker-Warburg syndrome) or milder limb-girdle muscular dystrophy. The condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7MIM #614643

Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7MIM #616052

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · myopathy caused by variation in CRPPA · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.82

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.14

OE 0.47 (0.28–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.41Z-score

OE missense 0.91 (0.81–1.04)

167 obs / 182.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.28–0.82)

0≤0.351.4

Missense OE?0.91 (0.81–1.04)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 9 / 19.1Missense obs/exp: 167 / 182.7Syn Z: -1.78

Background carrier burden — how many people carry a rare variant somewhere in CRPPA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

672 rare PASS variants

Rare truncating (LoF)

1 in 1,200

108 rare PASS variants

Rare synonymous (reference)

1 in 190

268 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CRPPA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 1,200
South Asian	~43k	1 in 120	1 in 460
Remaining (unassigned)	~30k	1 in 97	1 in 1,300
European (Finnish)	~27k	1 in 380	1 in 1,400
Admixed American	~22k	1 in 150	1 in 1,100
African / African American	~21k	1 in 88	1 in 1,400
East Asian	~20k	1 in 130	1 in 1,100
Ashkenazi Jewish	~13k	1 in 320	≈ 1 in 3,100
Middle Eastern	~2,884	1 in 78	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 10 coding exons well covered in gnomAD exomes; exons 1, 4, 6, 8, 9, 10 marginal. Genomes: all 10.? see exons ↓