# NM_001355024.4(CAPS2):c.778T>G (p.Phe260Val)

https://sugi.bio/variant/caps2-p-phe260val

## Summary

**CAPS2 p.Phe260Val (c.778T>G)** is classified **Uncertain significance** in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: ambiguous (0.443); Very rare (popmax 8.49e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 8.49e-05%, nfe)

## For patients & families {#patients}

This is a change in the CAPS2 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 | [CAPS2](https://sugi.bio/atlas/gene/CAPS2/) |
| Protein change (HGVS p.) | p.Phe260Val |
| Coding change (HGVS c.) | c.778T>G |
| MANE Select transcript | [NM_017954](https://www.ncbi.nlm.nih.gov/nuccore/NM_017954) (variant reported on NM_001355024) |
| Variant type | single nucleotide variant |
| Location | chr12:75298929-75298929 (GRCh38) |
| ClinVar | [VCV3827343](https://www.ncbi.nlm.nih.gov/clinvar/variation/3827343/) |

**All HGVS expressions:** `NC_000012.11:g.75692709A>C`, `NC_000012.12:g.75298929A>C`, `NM_001286547.3:c.762-149T>G`, `NM_001286548.3:c.253T>G`, `NM_001355023.4:c.855-149T>G`, `NM_001355024.4:c.778T>G`, `NM_001355025.2:c.691T>G`, `NM_001355026.2:c.597-149T>G`, `NM_001355027.2:c.691T>G`, `NM_001355030.2:c.253T>G`, `NM_001355031.2:c.253T>G`, `NM_001355032.2:c.253T>G`, `NM_001355033.2:c.253T>G`, `NM_032606.5:c.949T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.443) — no call either way
- REVEL 0.433 (indeterminate)
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.018, GERP 1.53, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **F317V** vs ClinVar **F260V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.9**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain, 37 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.49e-05%** (nfe) · 1/1,178,354 in the highest group · 1/1,456,964 alleles overall — very rare (popmax 8.49e-05%, nfe).

*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}

**CAPS2** population constraint: ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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 79.91, 44% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-03.

**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 | 2025-03-03 |

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

## Similar variants {#similar}

Related CAPS2 variant pages (same residue, condition, or type): [CADPS2 c.3718-15A>C](/variant/cadps2-c-3718-minus-15a-c), [CADPS2 p.Ala298Thr](/variant/cadps2-p-ala298thr), [CADPS2 p.Asp1088Asn](/variant/cadps2-p-asp1088asn), [CADPS2 p.Glu1010Lys](/variant/cadps2-p-glu1010lys), [CADPS2 p.Leu154=](/variant/cadps2-p-leu154), [CADPS2 p.Lys338=](/variant/cadps2-p-lys338), [CADPS2 p.Met828Val](/variant/cadps2-p-met828val), [CADPS2 p.Thr819=](/variant/cadps2-p-thr819).

### 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 3827343). 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.*