# NM_004383.3(CSK):c.296C>T (p.Pro99Leu)

https://sugi.bio/variant/csk-p-pro99leu

## Summary

**CSK p.Pro99Leu (c.296C>T)** is classified **Uncertain significance** in CSK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: ambiguous (0.3609); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs780001574 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CSK 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 | [CSK](https://sugi.bio/atlas/gene/CSK/) |
| Protein change (HGVS p.) | p.Pro99Leu |
| Coding change (HGVS c.) | c.296C>T |
| MANE Select transcript | [NM_004383](https://www.ncbi.nlm.nih.gov/nuccore/NM_004383) |
| dbSNP | [rs780001574](https://www.ncbi.nlm.nih.gov/snp/rs780001574/) |
| Variant type | single nucleotide variant |
| Location | chr15:74799325-74799325 (GRCh38) |
| ClinVar | [VCV2558832](https://www.ncbi.nlm.nih.gov/clinvar/variation/2558832/) |

**All HGVS expressions:** `NC_000015.10:g.74799325C>T`, `NC_000015.9:g.75091666C>T`, `NG_086679.2:g.1299C>T`, `NG_086679.3:g.1314C>T`, `NM_001127190.2:c.296C>T`, `NM_001354988.2:c.296C>T`, `NM_001387089.1:c.296C>T`, `NM_001387090.1:c.296C>T`, `NM_001387091.1:c.296C>T`, `NM_001387092.1:c.296C>T`, `NM_001387093.1:c.296C>T`, `NM_001387094.1:c.296C>T`, `NM_001387095.1:c.296C>T`, `NM_001387096.1:c.296C>T`, `NM_001387097.1:c.197C>T`, `NM_001387098.1:c.167C>T`, `NM_004383.3:c.296C>T`, `NR_170550.1:n.1002C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3609) — no call either way
- REVEL 0.66 (pathogenic-leaning)
- SaProt LLR -5.017 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 7.707, GERP 1.7, phastCons 1 — highly conserved
- CADD: **PHRED 26.5**. 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 0.49** across the covering region of the MANE Select transcript (74,798,298–74,801,711), spanning 3,413 bp. Chi-square p 1e-25. 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 (C>A, Δ1.00 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 **0.00223%** (eas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/44,884 in the highest group · 3/1,460,152 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,884 |
| European (non-Finnish) | 0.000169% | 589,981 |

*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}

**CSK** population constraint: LOEUF 0.222, pLI 1, missense-Z 4.7576. *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 **99** lies in the sh2 domain.

AlphaFold model confidence (whole protein): pLDDT 91.57, 75% of residues very-high.

**6 experimental structure(s)** (PDB): [1BYG](https://www.rcsb.org/structure/1BYG), [1CSK](https://www.rcsb.org/structure/1CSK), [3D7T](https://www.rcsb.org/structure/3D7T), [3D7U](https://www.rcsb.org/structure/3D7U), [3EAC](https://www.rcsb.org/structure/3EAC), [3EAZ](https://www.rcsb.org/structure/3EAZ) — incl. mutant structure 3EAZ.

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

*Describes the biological roles of CSK (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:** CSK's established molecular role includes protein kinase A catalytic subunit binding. p.Pro99Leu falls in the sh2 domain. In Reactome, CSK is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by BRAF and RAF1 fusions**.

**Disease mechanism (Reactome):** CSK loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952), [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223).

### Pathways affected {#pathways}

CSK participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | other |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | other |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | other |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | other |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | other |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | other |
| [GAB1 signalosome](https://reactome.org/content/detail/R-HSA-180292) | curated |
| [Co-inhibition by PD-1](https://reactome.org/content/detail/R-HSA-389948) | other |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | other |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | other |
| [Negative regulation of FLT3](https://reactome.org/content/detail/R-HSA-9706369) | other |
| [Phosphorylation of CD3 and TCR zeta chains](https://reactome.org/content/detail/R-HSA-202427) | other |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | other |

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

**Molecular function:** protein kinase A catalytic subunit binding, identical protein binding.

**Biological process:** negative regulation of Golgi to plasma membrane protein transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-07.

**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 | 2023-06-07 |

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

## Similar variants {#similar}

Related CSK variant pages (same residue, condition, or type): [CSK p.Gly287Asp](/variant/csk-p-gly287asp), [CSK p.Ala407Thr](/variant/csk-p-ala407thr), [CSK p.Arg56Cys](/variant/csk-p-arg56cys), [CSK p.Arg56His](/variant/csk-p-arg56his), [CSK p.Arg94Gln](/variant/csk-p-arg94gln), [CSK p.Asn46Lys](/variant/csk-p-asn46lys), [CSK p.Asn63Ser](/variant/csk-p-asn63ser), [CSK p.Asp123Asn](/variant/csk-p-asp123asn).

### 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 2558832). 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.*