# NM_001101426.4(CRPPA):c.344_345insT (p.Lys115fs)

https://sugi.bio/variant/crppa-p-lys115fs

## Summary

**CRPPA p.Lys115fs (c.344_345insT)** is classified **Likely pathogenic** in CRPPA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-30). No gnomAD frequency available for this variant; Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs2546749070 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CRPPA gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (United Kingdom) |
| Diagnostic panels | CRPPA is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Walker-Warburg syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Areflexia — Very frequent (99-80%)
- Pachygyria — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Lissencephaly — Very frequent (99-80%)
- Aplasia/Hypoplasia involving the skeletal musculature — Very frequent (99-80%)
- Ventriculomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015829/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRPPA](https://sugi.bio/atlas/gene/CRPPA/) |
| Protein change (HGVS p.) | p.Lys115fs |
| Coding change (HGVS c.) | c.344_345insT |
| MANE Select transcript | [NM_001101426](https://www.ncbi.nlm.nih.gov/nuccore/NM_001101426) |
| dbSNP | [rs2546749070](https://www.ncbi.nlm.nih.gov/snp/rs2546749070/) |
| Variant type | Insertion |
| Location | chr7:16406250-16406251 (GRCh38) |
| ClinVar | [VCV3024158](https://www.ncbi.nlm.nih.gov/clinvar/variation/3024158/) |

**All HGVS expressions:** `NC_000007.13:g.16445875_16445876insA`, `NC_000007.14:g.16406250_16406251insA`, `NG_032690.2:g.20072_20073insT`, `NM_001101417.4:c.344_345insT`, `NM_001101426.4:c.344_345insT`, `NM_001368197.1:c.344_345insT`, `NR_160656.1:n.560_561insT`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.659, GERP -4.17, phastCons 0.005 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.462, pLI 3.8872e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CRPPA** population constraint: LOEUF 1.462, pLI 3.8872e-06, missense-Z -1.6315; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **myopathy caused by variation in CRPPA** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.63, 74% of residues very-high.

**1 experimental structure(s)** (PDB): [4CVH](https://www.rcsb.org/structure/4CVH).

## What this gene does {#gene-function}

*Describes the biological roles of CRPPA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CRPPA's established molecular role includes protein homodimerization activity.


### Pathways affected {#pathways}

CRPPA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Matriglycan biosynthesis on DAG1](https://reactome.org/content/detail/R-HSA-9939291) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein homodimerization activity, D-ribitol-5-phosphate cytidylyltransferase activity, cytidylyltransferase activity.

**Biological process:** protein O-linked glycosylation via mannose.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-01-30.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dept. of Pathology and Cell Biology, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-01-30 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-brain-and-eye-anomalies-type-a-7/).

**Reported phenotype names (ClinVar):** Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A7, WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, ISPD-RELATED.

## Similar variants {#similar}

Related CRPPA variant pages (same residue, condition, or type): [CRPPA c.836-16_836-15insC](/variant/crppa-c-836-minus-16-836-minus-15insc), [CRPPA c.1120-1G>T](/variant/crppa-c-1120-minus-1g-t), [CRPPA c.258-1G>C](/variant/crppa-c-258-minus-1g-c), [CRPPA c.835+2T>C](/variant/crppa-c-835-plus-2t-c), [CRPPA p.Arg184Ter](/variant/crppa-p-arg184ter), [CRPPA p.Arg268Ter](/variant/crppa-p-arg268ter), [CRPPA p.Gln215Ter](/variant/crppa-p-gln215ter), [CRPPA p.Ser19Glufs](/variant/crppa-p-ser19glufs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3024158). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*