# NM_004058.5(CAPS):c.391C>A (p.Arg131Ser)

https://sugi.bio/variant/caps-p-arg131ser

## Summary

**CAPS p.Arg131Ser (c.391C>A)** is classified **Uncertain significance** in CAPS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: likely benign (0.3026); Very rare (popmax 0.00415%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs755619424 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00415%, nfe)

## For patients & families {#patients}

This is a change in the CAPS 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 | [CAPS](https://sugi.bio/atlas/gene/CAPS/) |
| Protein change (HGVS p.) | p.Arg131Ser |
| Coding change (HGVS c.) | c.391C>A |
| MANE Select transcript | [NM_003716](https://www.ncbi.nlm.nih.gov/nuccore/NM_003716) (variant reported on NM_004058) |
| dbSNP | [rs755619424](https://www.ncbi.nlm.nih.gov/snp/rs755619424/) |
| Variant type | single nucleotide variant |
| Location | chr19:5915069-5915069 (GRCh38) |
| ClinVar | [VCV2219247](https://www.ncbi.nlm.nih.gov/clinvar/variation/2219247/) |

**All HGVS expressions:** `NC_000019.10:g.5915069C>A`, `NC_000019.9:g.5915080C>A`, `NM_004058.5:c.391C>A`, `NM_080590.4:c.387+4C>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** (0.3026)
- REVEL 0.159 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.44 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.711, GERP 1.93, phastCons 0.908 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R217S** vs ClinVar **R131S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.0**. 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 **0.01**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.45**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.45**.
- Pangolin: Δ**0.34** (gain), gain 0.34 / loss 0.00. Agrees with SpliceAI. 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 **0.00415%** (nfe) · FAF95 0.00318% · FAF99 0.00286% · 49/1,179,788 in the highest group · 51/1,612,790 alleles overall — very rare (popmax 0.00415%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00415% | 24,077 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,229 |

*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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.13, 43% of residues very-high.

**1 experimental structure(s)** (PDB): [1WI1](https://www.rcsb.org/structure/1WI1).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-28.

**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 | 2022-04-28 |

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

## Similar variants {#similar}

Related CAPS variant pages (same residue, condition, or type): [CAPS p.Arg131Cys](/variant/caps-p-arg131cys), [CADPS p.Ser203=](/variant/cadps-p-ser203), [CADPS p.Tyr579=](/variant/cadps-p-tyr579), [CAPS p.Arg18His](/variant/caps-p-arg18his), [CAPS p.Pro88Thr](/variant/caps-p-pro88thr), [CADPS c.3477+2T>G](/variant/cadps-c-3477-plus-2t-g), [CADPS p.Ala1047Thr](/variant/cadps-p-ala1047thr), [CADPS p.Ala1057Val](/variant/cadps-p-ala1057val).

### 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 2219247). 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.*