# NM_198291.3(SRC):c.250+306del

https://sugi.bio/variant/src-c-250-plus-306del

## Summary

**SRC c.250+306del** is classified **Benign** in SRC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-19). Common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs10714592 · 1 submitter · common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the SRC gene that is classified as benign — not considered disease-causing, 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 | [SRC](https://sugi.bio/atlas/gene/SRC/) |
| Coding change (HGVS c.) | c.250+306del |
| MANE Select transcript | [NM_198291](https://www.ncbi.nlm.nih.gov/nuccore/NM_198291) |
| dbSNP | [rs10714592](https://www.ncbi.nlm.nih.gov/snp/rs10714592/) |
| Variant type | Deletion |
| Location | chr20:37384708-37384708 (GRCh38) |
| ClinVar | [VCV1182919](https://www.ncbi.nlm.nih.gov/clinvar/variation/1182919/) |

**All HGVS expressions:** `LRG_1018:g.45025del`, `NC_000020.10:g.36013112del`, `NC_000020.11:g.37384709del`, `NG_023033.1:g.45025del`, `NM_005417.5:c.250+306del`, `NM_198291.3:c.250+306del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele.

- **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 -0.275, GERP -1.37 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.105**. 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.*
- Splice region: **deep intronic (+306 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z 6.70**, o/e 0.50 (1 kb window 37,384,000–37,385,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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 (gnomAD v4.1): grpmax **100%** (nfe) · FAF95 99.4% · FAF99 99.1% · 67,984/67,984 in the highest group · 152,177/152,178 alleles overall — common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American | 100% | 1 |
| East Asian | 100% | 1 |
| European (non-Finnish) (grpmax) | 100% | 1 |
| South Asian | 100% | 1 |
| Finnish (not grpmax-eligible) | 100% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 100% | 1 |
| Amish (not grpmax-eligible) | 100% | 1 |
| Middle Eastern | 100% | 1 |
| Remaining individuals (not grpmax-eligible) | 100% | 1 |
| African / African-American | 100% | 1 |

*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}

**SRC** population constraint: LOEUF 0.383, pLI 0.99997, missense-Z 2.8596. *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):

- **thrombocytopenia 6** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.59, 68% of residues very-high.

**79 experimental structure(s)** (PDB): [1A07](https://www.rcsb.org/structure/1A07), [1A08](https://www.rcsb.org/structure/1A08), [1A09](https://www.rcsb.org/structure/1A09), [1A1A](https://www.rcsb.org/structure/1A1A), [1A1B](https://www.rcsb.org/structure/1A1B), [1A1C](https://www.rcsb.org/structure/1A1C) — incl. mutant structure 1KSW.

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

*Describes the biological roles of SRC (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:** SRC's established molecular role includes protein kinase activity. In Reactome, SRC is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **InlA-mediated entry of Listeria monocytogenes into host cells**.

**Disease mechanism (Reactome):** SRC loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955).

### Pathways affected {#pathways}

SRC participates in **70 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | other |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | other |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | other |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Downregulation of ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1253288) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [GAB1 signalosome](https://reactome.org/content/detail/R-HSA-180292) | curated |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | curated |
| [GRB2:SOS provides linkage to MAPK signaling for Integrins ](https://reactome.org/content/detail/R-HSA-354194) | curated |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | curated |
| [p130Cas linkage to MAPK signaling for integrins](https://reactome.org/content/detail/R-HSA-372708) | curated |
| [ADP signalling through P2Y purinoceptor 1](https://reactome.org/content/detail/R-HSA-418592) | other |
| [Activated NTRK2 signals through FYN](https://reactome.org/content/detail/R-HSA-9032500) | electronic |
| [Activated NTRK3 signals through PI3K](https://reactome.org/content/detail/R-HSA-9603381) | electronic |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | other |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | other |
| [Co-stimulation by CD28](https://reactome.org/content/detail/R-HSA-389356) | other |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | other |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |
| [EPH-Ephrin signaling](https://reactome.org/content/detail/R-HSA-2682334) | other |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | other |
| [EPHA-mediated growth cone collapse](https://reactome.org/content/detail/R-HSA-3928663) | other |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | other |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | other |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | other |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | electronic |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | other |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | other |
| [Netrin mediated repulsion signals](https://reactome.org/content/detail/R-HSA-418886) | electronic |
| [PECAM1 interactions](https://reactome.org/content/detail/R-HSA-210990) | other |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | other |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | other |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [Receptor Mediated Mitophagy](https://reactome.org/content/detail/R-HSA-8934903) | other |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | other |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | other |
| [Regulation of RUNX1 Expression and Activity](https://reactome.org/content/detail/R-HSA-8934593) | electronic |
| [Regulation of commissural axon pathfinding by SLIT and ROBO](https://reactome.org/content/detail/R-HSA-428542) | electronic |
| [Regulation of gap junction activity](https://reactome.org/content/detail/R-HSA-191650) | other |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | electronic |
| [Signal regulatory protein family interactions](https://reactome.org/content/detail/R-HSA-391160) | other |
| [Signaling by ALK](https://reactome.org/content/detail/R-HSA-201556) | other |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signaling by EGFR](https://reactome.org/content/detail/R-HSA-177929) | other |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | other |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | other |
| [Thrombin signalling through proteinase activated receptors (PARs)](https://reactome.org/content/detail/R-HSA-456926) | other |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | other |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | other |
| [p38MAPK events](https://reactome.org/content/detail/R-HSA-171007) | other |

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

**Molecular function:** protein kinase activity, protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, signaling receptor binding, integrin binding, phospholipase activator activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, transforming growth factor beta receptor signaling pathway, integrin-mediated signaling pathway, regulation of epithelial cell migration, positive regulation of epithelial cell migration, peptidyl-tyrosine phosphorylation.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-06-19 |

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

## Similar variants {#similar}

Related SRC variant pages (same residue, condition, or type): [SRC p.Asn417fs](/variant/src-p-asn417fs), [SRC c.250+265_250+268del](/variant/src-c-250-plus-265-250-plus-268del).

### 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 1182919). 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.*