# NM_144575.3(CAPN13):c.1270C>A (p.Pro424Thr)

https://sugi.bio/variant/capn13-p-pro424thr

## Summary

**CAPN13 p.Pro424Thr (c.1270C>A)** is classified **Uncertain significance** in CAPN13 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.0919); Ultra-rare (popmax 0.0127%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0127%, nfe)

## For patients & families {#patients}

This is a change in the CAPN13 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAPN13](https://sugi.bio/atlas/gene/CAPN13/) |
| Protein change (HGVS p.) | p.Pro424Thr |
| Coding change (HGVS c.) | c.1270C>A |
| MANE Select transcript | [NM_144575](https://www.ncbi.nlm.nih.gov/nuccore/NM_144575) |
| Variant type | single nucleotide variant |
| Location | chr2:30743558-30743558 (GRCh38) |
| ClinVar | [VCV4648080](https://www.ncbi.nlm.nih.gov/clinvar/variation/4648080/) |

**All HGVS expressions:** `NC_000002.11:g.30966424G>T`, `NC_000002.12:g.30743558G>T`, `NM_144575.3:c.1270C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0919)
- REVEL 0.314 (indeterminate)
- SaProt LLR -5.883 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.065, GERP -1.29 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.02**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (30,730,763–30,787,325), spanning 56,562 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.25**, donor loss **0.00**, acceptor gain **0.11**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.25**, donor loss **0.00**, acceptor gain **0.11**, donor gain **0.00**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.16. SpliceAI calls loss. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0127%** (nfe) · FAF95 0.011% · FAF99 0.0104% · 150/1,179,884 in the highest group · 156/1,613,830 alleles overall — ultra-rare (popmax 0.0127%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0127% | 7,866 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,821 |
| African / African-American | 0.00401% | 24,964 |

*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}

**CAPN13** population constraint: LOEUF 1.121, pLI 5.0738e-26, missense-Z -0.3675. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.25, 45% of residues very-high.

**1 experimental structure(s)** (PDB): [2I7A](https://www.rcsb.org/structure/2I7A).

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

*Describes the biological roles of CAPN13 (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.*


### Pathways affected {#pathways}

CAPN13 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-02 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CAPN13 variant pages (same residue, condition, or type): [CAPN13 p.Ala172Ser](/variant/capn13-p-ala172ser), [CAPN13 p.Ala215Ser](/variant/capn13-p-ala215ser), [CAPN13 p.Ala2Val](/variant/capn13-p-ala2val), [CAPN13 p.Ala326Val](/variant/capn13-p-ala326val), [CAPN13 p.Ala460Gly](/variant/capn13-p-ala460gly), [CAPN13 p.Ala510Pro](/variant/capn13-p-ala510pro), [CAPN13 p.Ala564Val](/variant/capn13-p-ala564val), [CAPN13 p.Ala90Ser](/variant/capn13-p-ala90ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 4648080). 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.*