# NM_005157.6(ABL1):c.1110G>A (p.Leu370=)

https://sugi.bio/variant/abl1-p-leu370

## Summary

**ABL1 p.Leu370= (c.1110G>A)** is classified **Likely benign** in ABL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs2133002989 · 1 submitter · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ABL1 gene that is classified as likely 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 | [ABL1](https://sugi.bio/atlas/gene/ABL1/) |
| Protein change (HGVS p.) | p.Leu370= |
| Coding change (HGVS c.) | c.1110G>A |
| MANE Select transcript | [NM_005157](https://www.ncbi.nlm.nih.gov/nuccore/NM_005157) |
| dbSNP | [rs2133002989](https://www.ncbi.nlm.nih.gov/snp/rs2133002989/) |
| Variant type | single nucleotide variant |
| Location | chr9:130874892-130874892 (GRCh38) |
| ClinVar | [VCV2762204](https://www.ncbi.nlm.nih.gov/clinvar/variation/2762204/) |

**All HGVS expressions:** `LRG_769:g.166012G>A`, `LRG_769t1:c.1110G>A`, `LRG_769t2:c.1167G>A`, `NC_000009.11:g.133750279G>A`, `NC_000009.12:g.130874892G>A`, `NG_012034.1:g.166012G>A`, `NM_005157.6:c.1110G>A`, `NM_007313.3:c.1167G>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 (below), not from a missing predictor score.
- Conservation: phyloP 2.624, GERP -1.27, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.145**. 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 (G>T, Δ0.21 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 **8.47e-05%** (nfe) · 1/1,180,030 in the highest group · 1/1,461,872 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**ABL1** population constraint: LOEUF 0.19, pLI 1, missense-Z 4.2885. *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 **370** lies in a β-strand; the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 64.68, 39% of residues very-high.

**85 experimental structure(s)** (PDB): [1AB2](https://www.rcsb.org/structure/1AB2), [1AWO](https://www.rcsb.org/structure/1AWO), [1BBZ](https://www.rcsb.org/structure/1BBZ), [1JU5](https://www.rcsb.org/structure/1JU5), [1OPL](https://www.rcsb.org/structure/1OPL), [1ZZP](https://www.rcsb.org/structure/1ZZP) — incl. mutant structure 2F4J.

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

*Describes the biological roles of ABL1 (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:** ABL1's established molecular role includes magnesium ion binding. p.Leu370= falls in the protein kinase domain. In Reactome, ABL1 is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** ABL1 loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

ABL1 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | curated |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | electronic |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [Role of ABL in ROBO-SLIT signaling](https://reactome.org/content/detail/R-HSA-428890) | electronic |

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

**Molecular function:** magnesium ion binding, four-way junction DNA binding, bubble DNA binding, phosphotyrosine residue binding, protein kinase activity, protein serine/threonine kinase activity.

**Biological process:** DNA damage response, response to oxidative stress, positive regulation of cytosolic calcium ion concentration, integrin-mediated signaling pathway, positive regulation of endothelial cell migration, regulation of axon extension.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-20 |

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

## Similar variants {#similar}

Related ABL1 variant pages (same residue, condition, or type): [ABL1 p.Ala337Thr](/variant/abl1-p-ala337thr), [ABL1 p.Ala433Thr](/variant/abl1-p-ala433thr), [ABL1 p.Asp504Gly](/variant/abl1-p-asp504gly), [ABL1 p.Glu509Lys](/variant/abl1-p-glu509lys), [ABL1 p.Gly254Arg](/variant/abl1-p-gly254arg), [ABL1 p.Pro230Leu](/variant/abl1-p-pro230leu), [ABL1 p.Trp99Arg](/variant/abl1-p-trp99arg), [ABL1 p.Tyr226Cys](/variant/abl1-p-tyr226cys).

### 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 2762204). 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.*