# NM_005157.6(ABL1):c.692A>G (p.Asn231Ser)

https://sugi.bio/variant/abl1-p-asn231ser

## Summary

**ABL1 p.Asn231Ser (c.692A>G)** is classified **Likely benign** in ABL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.0667); Ultra-rare (popmax 0.0384%, sas); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs572239604 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0384%, sas)

## For patients & families {#patients}

This is a change in the ABL1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Asn231Ser |
| Coding change (HGVS c.) | c.692A>G |
| MANE Select transcript | [NM_005157](https://www.ncbi.nlm.nih.gov/nuccore/NM_005157) |
| dbSNP | [rs572239604](https://www.ncbi.nlm.nih.gov/snp/rs572239604/) |
| Variant type | single nucleotide variant |
| Location | chr9:130862905-130862905 (GRCh38) |
| ClinVar | [VCV3131779](https://www.ncbi.nlm.nih.gov/clinvar/variation/3131779/) |

**All HGVS expressions:** `LRG_769:g.154025A>G`, `LRG_769t1:c.692A>G`, `LRG_769t2:c.749A>G`, `NC_000009.11:g.133738292A>G`, `NC_000009.12:g.130862905A>G`, `NG_012034.1:g.154025A>G`, `NG_117826.1:g.519A>G`, `NG_117827.1:g.18A>G`, `NM_005157.6:c.692A>G`, `NM_007313.3:c.749A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0667)
- REVEL 0.06 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.425 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.431, GERP 0.076, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.4**. 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 0.43** across the covering region of the MANE Select transcript (130,862,806–130,873,019), spanning 10,213 bp. Chi-square p 1.5e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0384%** (sas) · FAF95 0.0283% · FAF99 0.0249% · 35/91,072 in the highest group · 41/1,614,138 alleles overall — ultra-rare (popmax 0.0384%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0384% | 2,602 |
| European (non-Finnish) | 0.000508% | 196,672 |

*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 **231** lies in a β-strand.

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. 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-08.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-08 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related ABL1 variant pages (same residue, condition, or type): [ABL1 p.Ala767Val](/variant/abl1-p-ala767val), [ABL1 p.Arg1016His](/variant/abl1-p-arg1016his), [ABL1 p.Arg771Gly](/variant/abl1-p-arg771gly), [ABL1 p.Asn1088His](/variant/abl1-p-asn1088his), [ABL1 p.Asn120Thr](/variant/abl1-p-asn120thr), [ABL1 p.Asn414Lys](/variant/abl1-p-asn414lys), [ABL1 p.Glu123Gln](/variant/abl1-p-glu123gln), [ABL1 p.Gly677Arg](/variant/abl1-p-gly677arg).

### 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 3131779). 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.*