# NM_001143962.2(CAPN8):c.872T>C (p.Val291Ala)

https://sugi.bio/variant/capn8-p-val291ala

## Summary

**CAPN8 p.Val291Ala (c.872T>C)** is classified **Uncertain significance** in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.1602); Very rare (popmax 0.00548%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00548%, afr)

## For patients & families {#patients}

This is a change in the CAPN8 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 | [CAPN8](https://sugi.bio/atlas/gene/CAPN8/) |
| Protein change (HGVS p.) | p.Val291Ala |
| Coding change (HGVS c.) | c.872T>C |
| MANE Select transcript | [NM_001143962](https://www.ncbi.nlm.nih.gov/nuccore/NM_001143962) |
| Variant type | single nucleotide variant |
| Location | chr1:223622842-223622842 (GRCh38) |
| ClinVar | [VCV3995273](https://www.ncbi.nlm.nih.gov/clinvar/variation/3995273/) |

**All HGVS expressions:** `NC_000001.10:g.223810544A>G`, `NC_000001.11:g.223622842A>G`, `NM_001143962.2:c.872T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1602)
- REVEL 0.683 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.02 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 9.164, GERP 2.47, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.5**. 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 1.08** across the covering region of the MANE Select transcript (223,541,839–223,665,646), spanning 123,807 bp. Chi-square p 0.038. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.52 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00548%** (afr) · FAF95 0.00178% · FAF99 0.00106% · 4/73,052 in the highest group · 4/1,551,626 alleles overall — very rare (popmax 0.00548%, afr).

*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}

**CAPN8** population constraint: LOEUF 1.184, pLI 1.221e-24, missense-Z -0.17965. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **291** lies in the calpain catalytic domain.

AlphaFold model confidence (whole protein): pLDDT 89.15, 60% of residues very-high.

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

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

*Describes the biological roles of CAPN8 (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}

CAPN8 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 2025-04-12.

**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 | 2025-04-12 |

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

## Similar variants {#similar}

Related CAPN8 variant pages (same residue, condition, or type): [CAPN8 p.Val291Glu](/variant/capn8-p-val291glu), [CAPN8 p.Ala112Val](/variant/capn8-p-ala112val), [CAPN8 p.Ala136Glu](/variant/capn8-p-ala136glu), [CAPN8 p.Ala136Thr](/variant/capn8-p-ala136thr), [CAPN8 p.Ala194Ser](/variant/capn8-p-ala194ser), [CAPN8 p.Ala231Ser](/variant/capn8-p-ala231ser), [CAPN8 p.Ala234Val](/variant/capn8-p-ala234val), [CAPN8 p.Ala247Val](/variant/capn8-p-ala247val).

### 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 3995273). 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.*