# NM_001385503.1(CAPRIN2):c.2038C>G (p.Gln680Glu)

https://sugi.bio/variant/caprin2-p-gln680glu

## Summary

**CAPRIN2 p.Gln680Glu (c.2038C>G)** is classified **Uncertain significance** in CAPRIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1359690974 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CAPRIN2 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 | [CAPRIN2](https://sugi.bio/atlas/gene/CAPRIN2/) |
| Protein change (HGVS p.) | p.Gln680Glu |
| Coding change (HGVS c.) | c.2038C>G |
| MANE Select transcript | [NM_001385503](https://www.ncbi.nlm.nih.gov/nuccore/NM_001385503) |
| dbSNP | [rs1359690974](https://www.ncbi.nlm.nih.gov/snp/rs1359690974/) |
| Variant type | single nucleotide variant |
| Location | chr12:30719093-30719093 (GRCh38) |
| ClinVar | [VCV3137225](https://www.ncbi.nlm.nih.gov/clinvar/variation/3137225/) |

**All HGVS expressions:** `NC_000012.11:g.30872027G>C`, `NC_000012.12:g.30719093G>C`, `NG_029557.2:g.40422C>G`, `NM_001002259.3:c.2281C>G`, `NM_001206856.3:c.2176C>G`, `NM_001319842.2:c.1282C>G`, `NM_001319843.2:c.2281C>G`, `NM_001319844.2:c.1933C>G`, `NM_001319845.2:c.2038C>G`, `NM_001319846.2:c.2038C>G`, `NM_001385498.1:c.2281C>G`, `NM_001385499.1:c.2176C>G`, `NM_001385500.1:c.2176C>G`, `NM_001385501.1:c.2038C>G`, `NM_001385502.1:c.2038C>G`, `NM_001385503.1:c.2038C>G`, `NM_001385504.1:c.2038C>G`, `NM_001385505.1:c.2038C>G`, `NM_001385506.1:c.2038C>G`, `NM_001385507.1:c.1933C>G`, `NM_001385508.1:c.1933C>G`, `NM_001385509.1:c.1933C>G`, `NM_001385510.1:c.1933C>G`, `NM_001385511.1:c.1801-2417C>G`, `NM_001385512.1:c.1801-2417C>G`, `NM_001385513.1:c.1801-2417C>G`, `NM_001385514.1:c.1801-2417C>G`, `NM_001385515.1:c.1801-2417C>G`, `NM_001385516.1:c.2281C>G`, `NM_001385518.1:c.2281C>G`, `NM_001385519.1:c.2038C>G`, `NM_001385520.1:c.2038C>G`, `NM_001385521.1:c.2038C>G`, `NM_001385522.1:c.2038C>G`, `NM_001385523.1:c.2038C>G`, `NM_001385524.1:c.2038C>G`, `NM_001385525.1:c.2038C>G`, `NM_001385526.1:c.1933C>G`, `NM_001385527.1:c.1801-2417C>G`, `NM_001385528.1:c.1282C>G`, `NM_001385529.1:c.1282C>G`, `NM_001385531.1:c.1282C>G`, `NM_001385532.1:c.1282C>G`, `NM_001385533.1:c.1282C>G`, `NM_001385534.1:c.1282C>G`, `NM_001385535.1:c.1801-2417C>G`, `NM_001385537.1:c.1282C>G`, `NM_001385538.1:c.1213C>G`, `NM_001385539.1:c.1177C>G`, `NM_001385540.1:c.1177C>G`, `NM_001385541.1:c.1177C>G`, `NM_001385542.1:c.1177C>G`, `NM_001385543.1:c.1108C>G`, `NM_001385544.1:c.1108C>G`, `NM_001385545.1:c.1045-2417C>G`, `NM_001385546.1:c.976-2417C>G`, `NM_001385547.1:c.1282C>G`, `NM_001385548.1:c.1282C>G`, `NM_001385549.1:c.1282C>G`, `NM_001385550.1:c.1282C>G`, `NM_001385551.1:c.1282C>G`, `NM_001385552.1:c.1282C>G`, `NM_001385553.1:c.1282C>G`, `NM_001385554.1:c.1282C>G`, `NM_001385557.1:c.1177C>G`, `NM_001385559.1:c.1282C>G`, `NM_001416513.1:c.1045-2417C>G`, `NM_023925.5:c.2148+1718C>G`, `NM_032156.5:c.2281C>G`, `NR_038177.2:n.2949C>G`, `NR_169639.1:n.2265C>G`, `NR_169640.1:n.2265C>G`, `NR_169641.1:n.2265C>G`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 7.464, GERP 1.63, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 25.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.26 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 **0.00167%** (amr) · 1/60,002 in the highest group · 1/1,461,438 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**CAPRIN2** population constraint: LOEUF 0.58, pLI 0.0042945, missense-Z 1.0934. *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 **680** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 52.42, 22% of residues very-high.

**5 experimental structure(s)** (PDB): [4OUL](https://www.rcsb.org/structure/4OUL), [4OUM](https://www.rcsb.org/structure/4OUM), [5J97](https://www.rcsb.org/structure/5J97), [8K9C](https://www.rcsb.org/structure/8K9C), [8K9D](https://www.rcsb.org/structure/8K9D).

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

*Describes the biological roles of CAPRIN2 (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:** CAPRIN2's established molecular role includes signaling receptor binding. p.Gln680Glu falls in the disordered region.


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

**Molecular function:** signaling receptor binding.

**Biological process:** negative regulation of cell growth, positive regulation of transcription by RNA polymerase II, positive regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-13.

**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 | 2023-10-13 |

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

## Similar variants {#similar}

Related CAPRIN2 variant pages (same residue, condition, or type): [CAPRIN2 c.1800+5C>T](/variant/caprin2-c-1800-plus-5c-t), [CAPRIN2 p.Met253Thr](/variant/caprin2-p-met253thr), [CAPRIN2 p.Ser668=](/variant/caprin2-p-ser668), [CAPRIN2 p.Thr763=](/variant/caprin2-p-thr763), [CAPRIN2 p.Tyr806=](/variant/caprin2-p-tyr806), [CAPRIN2 c.-12A>G](/variant/caprin2-c-minus-12a-g), [CAPRIN2 c.-2A>C](/variant/caprin2-c-minus-2a-c), [CAPRIN2 c.-30G>A](/variant/caprin2-c-minus-30g-a).

### 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 3137225). 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.*