# NM_005898.5(CAPRIN1):c.606G>A (p.Arg202=)

https://sugi.bio/variant/caprin1-p-arg202

## Summary

**CAPRIN1 p.Arg202= (c.606G>A)** is classified **Uncertain significance** in CAPRIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-16). Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CAPRIN1 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 | [CAPRIN1](https://sugi.bio/atlas/gene/CAPRIN1/) |
| Protein change (HGVS p.) | p.Arg202= |
| Coding change (HGVS c.) | c.606G>A |
| MANE Select transcript | [NM_005898](https://www.ncbi.nlm.nih.gov/nuccore/NM_005898) |
| Variant type | single nucleotide variant |
| Location | chr11:34076560-34076560 (GRCh38) |
| ClinVar | [VCV4648192](https://www.ncbi.nlm.nih.gov/clinvar/variation/4648192/) |

**All HGVS expressions:** `NC_000011.10:g.34076560G>A`, `NC_000011.9:g.34098107G>A`, `NM_005898.5:c.606G>A`, `NM_203364.3:c.606G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.49) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.912, GERP 0.245, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.02**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.49**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss at this position.
- 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.*
- Pangolin: Δ**0.35** (loss), gain 0.01 / loss 0.35. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CAPRIN1** population constraint: LOEUF 0.372, pLI 1, missense-Z 1.2679; ClinGen dosage — haploinsufficiency 2/3, triplosensitivity 0/3. *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):

- **neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline** — Moderate (AD)
- **neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 58.64, 29% of residues very-high.

**6 experimental structure(s)** (PDB): [4WBE](https://www.rcsb.org/structure/4WBE), [4WBP](https://www.rcsb.org/structure/4WBP), [6TA7](https://www.rcsb.org/structure/6TA7), [7XHG](https://www.rcsb.org/structure/7XHG), [8TH7](https://www.rcsb.org/structure/8TH7), [9HFU](https://www.rcsb.org/structure/9HFU).

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

*Describes the biological roles of CAPRIN1 (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:** CAPRIN1's established molecular role includes RNA binding.


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

**Molecular function:** RNA binding, mRNA binding, ATP binding, signaling adaptor activity, molecular function activator activity, molecular condensate scaffold activity.

**Biological process:** negative regulation of translation, positive regulation of cytoplasmic stress granule assembly, regulation of deadenylation-dependent decapping of nuclear-transcribed mRNA, membraneless organelle assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-16.

**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 | 2025-09-16 |

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

## Similar variants {#similar}

Related CAPRIN1 variant pages (same residue, condition, or type): [CAPRIN1 p.Arg458Ter](/variant/caprin1-p-arg458ter), [CAPRIN1 p.Arg132Cys](/variant/caprin1-p-arg132cys), [CAPRIN1 p.Gln206Arg](/variant/caprin1-p-gln206arg), [CAPRIN1 p.Pro424Leu](/variant/caprin1-p-pro424leu), [CAPRIN1 p.Pro528Thr](/variant/caprin1-p-pro528thr), [CAPRIN1 c.1122+19G>A](/variant/caprin1-c-1122-plus-19g-a), [CAPRIN1 c.217-5C>G](/variant/caprin1-c-217-minus-5c-g), [CAPRIN1 c.688+5G>A](/variant/caprin1-c-688-plus-5g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4648192). 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.*