# NM_005898.5(CAPRIN1):c.44C>T (p.Ser15Phe)

https://sugi.bio/variant/caprin1-p-ser15phe

## Summary

**CAPRIN1 p.Ser15Phe (c.44C>T)** is classified **Likely benign** in CAPRIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely benign (0.2086); Ultra-rare (popmax 0.0429%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0429%, afr)

## For patients & families {#patients}

This is a change in the CAPRIN1 gene that is classified as likely benign — not considered disease-causing, 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.Ser15Phe |
| Coding change (HGVS c.) | c.44C>T |
| MANE Select transcript | [NM_005898](https://www.ncbi.nlm.nih.gov/nuccore/NM_005898) |
| Variant type | single nucleotide variant |
| Location | chr11:34052464-34052464 (GRCh38) |
| ClinVar | [VCV3995294](https://www.ncbi.nlm.nih.gov/clinvar/variation/3995294/) |

**All HGVS expressions:** `NC_000011.10:g.34052464C>T`, `NC_000011.9:g.34074011C>T`, `NM_005898.5:c.44C>T`, `NM_203364.3:c.44C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2086)
- REVEL 0.047 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.087 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 5.376, GERP 0.218, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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 1.26** across the covering region of the MANE Select transcript (34,052,421–34,052,594), spanning 173 bp. Chi-square p 0.016. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0429%** (afr) · FAF95 0.0311% · FAF99 0.0272% · 32/74,636 in the highest group · 37/1,607,524 alleles overall — ultra-rare (popmax 0.0429%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0429% | 2,332 |
| Admixed American | 0.00507% | 19,707 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,070 |
| European (non-Finnish) | 8.48e-05% | 1,178,716 |

*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}

Residue **15** lies in the 'disordered' region.

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. p.Ser15Phe falls in the disordered region.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-25.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-25 |

**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 3995294). 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.*