# NM_001715.3(BLK):c.669G>A (p.Pro223=)

https://sugi.bio/variant/blk-p-pro223

## Summary

**BLK p.Pro223= (c.669G>A)** is classified **Conflicting classifications of pathogenicity** in BLK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-31). Ultra-rare (popmax 0.0107%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs775121719 · 2 submitters · ultra-rare (popmax 0.0107%, afr)

## For patients & families {#patients}

This is a change in the BLK gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 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.Pro223= |
| Coding change (HGVS c.) | c.669G>A |
| MANE Select transcript | [NM_001715](https://www.ncbi.nlm.nih.gov/nuccore/NM_001715) |
| dbSNP | [rs775121719](https://www.ncbi.nlm.nih.gov/snp/rs775121719/) |
| Variant type | single nucleotide variant |
| Location | chr8:11555381-11555381 (GRCh38) |
| ClinVar | [VCV2658406](https://www.ncbi.nlm.nih.gov/clinvar/variation/2658406/) |

**All HGVS expressions:** `NC_000008.10:g.11412890G>A`, `NC_000008.11:g.11555381G>A`, `NG_023543.2:g.66370G>A`, `NM_001330465.2:c.456G>A`, `NM_001715.3:c.669G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.54) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.516, GERP -3.94, phastCons 0.878 — weakly conserved position
- CADD: **PHRED 17.95**. 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 deltas (raw): acceptor loss **0.54**, donor loss **0.00**, acceptor gain **0.47**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.47**, donor gain **0.00**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.02. SpliceAI calls loss. 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 **0.0107%** (afr) · FAF95 0.00528% · FAF99 0.00387% · 8/74,904 in the highest group · 76/1,614,030 alleles overall — ultra-rare (popmax 0.0107%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0107% | 9,363 |
| European (non-Finnish) | 0.00534% | 18,731 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| South Asian | 0.0022% | 45,541 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,028 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-08-31.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-31 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-01 |

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

## Similar variants {#similar}

Related BLK variant pages (same residue, condition, or type): [BLK p.Pro223Leu](/variant/blk-p-pro223leu), [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).

### 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 2658406). 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.*