# NM_006110.3(CD2BP2):c.256C>T (p.Arg86Trp)

https://sugi.bio/variant/cd2bp2-p-arg86trp

## Summary

**CD2BP2 p.Arg86Trp (c.256C>T)** is classified **Uncertain significance** in CD2BP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.2782); Ultra-rare (popmax 0.0164%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs145685995 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the CD2BP2 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 | [CD2BP2](https://sugi.bio/atlas/gene/CD2BP2/) |
| Protein change (HGVS p.) | p.Arg86Trp |
| Coding change (HGVS c.) | c.256C>T |
| MANE Select transcript | [NM_006110](https://www.ncbi.nlm.nih.gov/nuccore/NM_006110) |
| dbSNP | [rs145685995](https://www.ncbi.nlm.nih.gov/snp/rs145685995/) |
| Variant type | single nucleotide variant |
| Location | chr16:30354020-30354020 (GRCh38) |
| ClinVar | [VCV2566381](https://www.ncbi.nlm.nih.gov/clinvar/variation/2566381/) |

**All HGVS expressions:** `NC_000016.10:g.30354020G>A`, `NC_000016.9:g.30365341G>A`, `NM_001243646.2:c.256C>T`, `NM_006110.3:c.256C>T`, `NR_024465.1:n.509C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2782)
- REVEL 0.239 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -12.432 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 4.26, GERP 1.43, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 1.12** across the covering region of the MANE Select transcript (30,352,988–30,354,681), spanning 1,693 bp. Chi-square p 0.012. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.28 acceptor 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.*
- Pangolin: Δ**0.27** (loss), gain 0.25 / loss 0.27. SpliceAI below 0.2. 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 **0.0164%** (mid) · FAF95 0.00326% · FAF99 0.00294% · 1/6,084 in the highest group · 53/1,613,962 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| European (non-Finnish) | 0.00424% | 23,600 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0011% | 91,086 |

*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}

**CD2BP2** population constraint: LOEUF 0.993, pLI 2.6363e-07, missense-Z -0.56272. *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 **86** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 70.04, 10% of residues very-high.

**10 experimental structure(s)** (PDB): [1GYF](https://www.rcsb.org/structure/1GYF), [1L2Z](https://www.rcsb.org/structure/1L2Z), [1SYX](https://www.rcsb.org/structure/1SYX), [4BWS](https://www.rcsb.org/structure/4BWS), [8Q7Q](https://www.rcsb.org/structure/8Q7Q), [8Q7V](https://www.rcsb.org/structure/8Q7V).

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

*Describes the biological roles of CD2BP2 (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:** CD2BP2's established molecular role includes ribonucleoprotein complex binding. In Reactome, CD2BP2 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CD2BP2 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CD2BP2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |

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

**Molecular function:** ribonucleoprotein complex binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-22.

**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 | 2025-08-22 |

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

## Similar variants {#similar}

Related CD2BP2 variant pages (same residue, condition, or type): [CD2BP2 p.Ala256Val](/variant/cd2bp2-p-ala256val), [CD2BP2 p.Ala67Val](/variant/cd2bp2-p-ala67val), [CD2BP2 p.Arg129Gln](/variant/cd2bp2-p-arg129gln), [CD2BP2 p.Arg177Gly](/variant/cd2bp2-p-arg177gly), [CD2BP2 p.Arg181Gln](/variant/cd2bp2-p-arg181gln), [CD2BP2 p.Arg187Lys](/variant/cd2bp2-p-arg187lys), [CD2BP2 p.Arg201Leu](/variant/cd2bp2-p-arg201leu), [CD2BP2 p.Arg201Trp](/variant/cd2bp2-p-arg201trp).

### 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 2566381). 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.*