# NM_001715.3(BLK):c.126T>C (p.Val42=)

https://sugi.bio/variant/blk-p-val42

## Summary

**BLK p.Val42= (c.126T>C)** is classified **Likely benign** in BLK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-13). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs571333916 · 3 submitters · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the BLK gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [BLK](https://sugi.bio/atlas/gene/BLK/) |
| Protein change (HGVS p.) | p.Val42= |
| Coding change (HGVS c.) | c.126T>C |
| MANE Select transcript | [NM_001715](https://www.ncbi.nlm.nih.gov/nuccore/NM_001715) |
| dbSNP | [rs571333916](https://www.ncbi.nlm.nih.gov/snp/rs571333916/) |
| Variant type | single nucleotide variant |
| Location | chr8:11546054-11546054 (GRCh38) |
| ClinVar | [VCV1186940](https://www.ncbi.nlm.nih.gov/clinvar/variation/1186940/) |

**All HGVS expressions:** `NC_000008.10:g.11403563T>C`, `NC_000008.11:g.11546054T>C`, `NG_023543.2:g.57043T>C`, `NM_001330465.2:c.-88T>C`, `NM_001715.3:c.126T>C`

## 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 -1.032, GERP -3.28 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.276**. 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 (T>A, Δ0.78 acceptor gain), 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 **0.0165%** (mid) · FAF95 0.00814% · FAF99 0.00633% · 1/6,062 in the highest group · 23/1,614,142 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| African / African-American | 0.0147% | 6,820 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,930 |
| European (non-Finnish) | 0.000339% | 295,001 |

*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}

**BLK** population constraint: LOEUF 1.295, pLI 6.5972e-23, missense-Z -2.5547. *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):

- **monogenic diabetes** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.89, 53% of residues very-high.

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

*Describes the biological roles of BLK (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:** BLK's established molecular role includes protein tyrosine kinase activity.


### Pathways affected {#pathways}

BLK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RUNX1 regulates transcription of genes involved in BCR signaling](https://reactome.org/content/detail/R-HSA-8939245) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |

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

**Molecular function:** protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity.

**Biological process:** peptidyl-tyrosine phosphorylation, positive regulation of insulin secretion, B cell receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-13.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2020–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-26 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-13 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related BLK variant pages (same residue, condition, or type): [BLK p.Arg131Gln](/variant/blk-p-arg131gln), [BLK p.Arg180His](/variant/blk-p-arg180his), [BLK p.Arg238Trp](/variant/blk-p-arg238trp), [BLK p.Arg295Trp](/variant/blk-p-arg295trp), [BLK p.Arg298Gln](/variant/blk-p-arg298gln), [BLK p.Arg466His](/variant/blk-p-arg466his), [BLK p.Asp68Val](/variant/blk-p-asp68val), [BLK p.Gln226Pro](/variant/blk-p-gln226pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1186940). 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.*