# NM_000044.6(AR):c.117del (p.Arg40fs)

https://sugi.bio/variant/ar-p-arg40fs

## Summary

**AR p.Arg40fs (c.117del)** is classified **Likely pathogenic** in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-12). Associated with AR-related disorders.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the AR gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to AR-related disorders.

*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 | [AR](https://sugi.bio/atlas/gene/AR/) |
| Protein change (HGVS p.) | p.Arg40fs |
| Coding change (HGVS c.) | c.117del |
| MANE Select transcript | [NM_000044](https://www.ncbi.nlm.nih.gov/nuccore/NM_000044) |
| Variant type | Deletion |
| Location | chrX:67545260-67545260 (GRCh38) |
| ClinVar | [VCV4951184](https://www.ncbi.nlm.nih.gov/clinvar/variation/4951184/) |

**All HGVS expressions:** `LRG_1406:g.6232del`, `LRG_1406t1:c.117del`, `NC_000023.10:g.66765105del`, `NC_000023.11:g.67545263del`, `NG_009014.2:g.6232del`, `NG_052629.1:g.47del`, `NM_000044.6:c.117del`, `NM_001011645.3:c.-1667del`, `NM_001348061.1:c.117del`, `NM_001348063.1:c.117del`, `NM_001348064.1:c.117del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.065, GERP -1.09, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 8**, so the transcript is predicted to undergo NMD.
- 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.

*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}


Curated gene–disease validity (ClinGen):

- **Kennedy disease** — Definitive (XL)

## Protein context {#protein}

Residue **40** lies in the 'interaction with znf318' region; the 'modulating' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 58.85, 29% of residues very-high.

**95 experimental structure(s)** (PDB): [1E3G](https://www.rcsb.org/structure/1E3G), [1GS4](https://www.rcsb.org/structure/1GS4), [1T5Z](https://www.rcsb.org/structure/1T5Z), [1T63](https://www.rcsb.org/structure/1T63), [1T65](https://www.rcsb.org/structure/1T65), [1XJ7](https://www.rcsb.org/structure/1XJ7) — incl. mutant structure 1GS4.

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

*Describes the biological roles of AR (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:** AR's established molecular role includes transcription cis-regulatory region binding. p.Arg40fs falls in the interaction with znf318 region.


### Pathways affected {#pathways}

AR participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3](https://reactome.org/content/detail/R-HSA-5625886) | other |
| [HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand](https://reactome.org/content/detail/R-HSA-3371497) | other |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | other |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | other |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | other |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | other |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, RNA polymerase II general transcription initiation factor binding, transcription coactivator binding, DNA-binding transcription activator activity, RNA polymerase II-specific.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of cell population proliferation, negative regulation of cell population proliferation, positive regulation of gene expression, estrogen receptor signaling pathway, androgen receptor signaling pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-12 |

## Associated conditions {#conditions}

[AR-related disorders](https://sugi.bio/atlas/disease/ar-related-disorders/).

**Reported phenotype names (ClinVar):** AR-related disorders.

## Similar variants {#similar}

Related AR variant pages (same residue, condition, or type): [AR p.Met247fs](/variant/ar-p-met247fs), [AR p.Pro368fs](/variant/ar-p-pro368fs), [AR p.Arg40Lys](/variant/ar-p-arg40lys), [AR p.Ile915fs](/variant/ar-p-ile915fs), [AR p.Leu57_Gln61del](/variant/ar-p-leu57-gln61del), [AR p.Ala597Thr](/variant/ar-p-ala597thr), [AR p.Arg511Ter](/variant/ar-p-arg511ter), [AR p.Arg608Gln](/variant/ar-p-arg608gln).

### 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 4951184). 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.*