# NM_013314.4(BLNK):c.26del (p.Val9fs)

https://sugi.bio/variant/blnk-p-val9fs

## Summary

**BLNK p.Val9fs (c.26del)** is classified **Pathogenic** in BLNK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-10). No gnomAD frequency available for this variant; Associated with agammaglobulinemia 4, autosomal recessive.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2493183249 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BLNK gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to agammaglobulinemia 4, autosomal recessive.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015674/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BLNK](https://sugi.bio/atlas/gene/BLNK/) |
| Protein change (HGVS p.) | p.Val9fs |
| Coding change (HGVS c.) | c.26del |
| MANE Select transcript | [NM_013314](https://www.ncbi.nlm.nih.gov/nuccore/NM_013314) |
| dbSNP | [rs2493183249](https://www.ncbi.nlm.nih.gov/snp/rs2493183249/) |
| Variant type | Deletion |
| Location | chr10:96271373-96271373 (GRCh38) |
| ClinVar | [VCV2090455](https://www.ncbi.nlm.nih.gov/clinvar/variation/2090455/) |

**All HGVS expressions:** `LRG_21:g.10197del`, `LRG_21t1:c.26del`, `NC_000010.10:g.98031130del`, `NC_000010.11:g.96271373del`, `NG_007575.1:g.10197del`, `NM_001114094.2:c.26del`, `NM_001258440.2:c.26del`, `NM_001258441.2:c.26del`, `NM_001258442.2:c.26del`, `NM_013314.4:c.26del`, `NR_047680.2:n.197del`, `NR_047681.2:n.197del`, `NR_047682.2:n.197del`, `NR_047683.2:n.197del`

## 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 0.698, phastCons 0.998 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.517, pLI 0.90436), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**BLNK** population constraint: LOEUF 0.517, pLI 0.90436, missense-Z 1.8811; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **agammaglobulinemia 4, autosomal recessive** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 64.46, 23% of residues very-high.

**1 experimental structure(s)** (PDB): [6YLU](https://www.rcsb.org/structure/6YLU).

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

*Describes the biological roles of BLNK (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:** BLNK's established molecular role includes lipid binding. In Reactome, BLNK is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** BLNK loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

BLNK participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | electronic |

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

**Molecular function:** lipid binding, enzyme binding, protein kinase binding, signaling adaptor activity, SH2 domain binding, phospholipase binding.

**Biological process:** intracellular signal transduction, B cell receptor signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-10.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-10 |

## Associated conditions {#conditions}

[agammaglobulinemia 4, autosomal recessive](https://sugi.bio/atlas/disease/agammaglobulinemia-4-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Agammaglobulinemia 4, autosomal recessive, AGAMMAGLOBULINEMIA, AUTOSOMAL RECESSIVE, DUE TO BLNK DEFECT, B cell linker protein deficiency.

## Similar variants {#similar}

Related BLNK variant pages (same residue, condition, or type): [BLNK p.Val9Ile](/variant/blnk-p-val9ile), [BLNK c.1096-17del](/variant/blnk-c-1096-minus-17del), [BLNK c.526-22_526-19del](/variant/blnk-c-526-minus-22-526-minus-19del), [BLNK p.Lys344fs](/variant/blnk-p-lys344fs), [BLNK p.Val206del](/variant/blnk-p-val206del), [BLNK c.775-12del](/variant/blnk-c-775-minus-12del), [BLNK c.902+2T>C](/variant/blnk-c-902-plus-2t-c), [BLNK p.Ala176Val](/variant/blnk-p-ala176val).

### 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 2090455). 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.*