# NM_000044.6(AR):c.2196C>T (p.Asp732=)

https://sugi.bio/variant/ar-p-asp732

## Summary

**AR p.Asp732= (c.2196C>T)** is classified **Benign** in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-28). Ultra-rare (popmax 0.0177%, eas); Associated with Kennedy disease.

**At a glance:** Benign · review: Single submitter · rsID rs199940567 · 1 submitter · 2 linked conditions · ultra-rare (popmax 0.0177%, eas)

## For patients & families {#patients}

This is a change in the AR gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to Kennedy disease.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked recessive |
| Age of onset (of this condition) | Adult |
| Prevalence | <1 / 1 000 000 (Italy) |
| Clinical trials | 11 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AR is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Kennedy disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased fertility — Very frequent (99-80%)
- Gynecomastia — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Dysarthria — Very frequent (99-80%)
- Hyporeflexia — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Dysphonia — Very frequent (99-80%)
- Skeletal muscle atrophy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006818/index) · [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.Asp732= |
| Coding change (HGVS c.) | c.2196C>T |
| MANE Select transcript | [NM_000044](https://www.ncbi.nlm.nih.gov/nuccore/NM_000044) |
| dbSNP | [rs199940567](https://www.ncbi.nlm.nih.gov/snp/rs199940567/) |
| Variant type | single nucleotide variant |
| Location | chrX:67717500-67717500 (GRCh38) |
| ClinVar | [VCV2925892](https://www.ncbi.nlm.nih.gov/clinvar/variation/2925892/) |

**All HGVS expressions:** `LRG_1406:g.178469C>T`, `LRG_1406t1:c.2196C>T`, `NC_000023.10:g.66937342C>T`, `NC_000023.11:g.67717500C>T`, `NG_009014.2:g.178469C>T`, `NM_000044.6:c.2196C>T`, `NM_001011645.3:c.600C>T`, `NM_001424175.1:c.2199C>T`

## 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 -4.48, GERP -3.73 — fast-evolving / accelerated position
- CADD: **PHRED 0.734**. 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: **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 **0.0177%** (eas) · FAF95 0.00765% · FAF99 0.00526% · 6/33,811 in the highest group · 26/1,097,996 alleles overall — ultra-rare (popmax 0.0177%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0177% | 5,635 |
| Admixed American | 0.00217% | 46,102 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,634 |
| European (non-Finnish) | 0.00201% | 49,749 |

*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 **732** lies in the nr lbd domain; the 'interaction with ccar1' region; the 'interaction with kat7' region; an α-helix; the 'interaction with lpxn' 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.Asp732= falls in the nr lbd domain.


### 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}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2023-09-28 |

## Associated conditions {#conditions}

[Kennedy disease](https://sugi.bio/atlas/disease/kennedy-disease/), [androgen insensitivity syndrome](https://sugi.bio/atlas/disease/androgen-insensitivity-syndrome/).

**Reported phenotype names (ClinVar):** Kennedy disease, Androgen resistance syndrome, SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1, KENNEDY SPINAL AND BULBAR MUSCULAR ATROPHY, Spinal and Bulbar Muscular Atrophy, DHTR DEFICIENCY, DIHYDROTESTOSTERONE RECEPTOR DEFICIENCY, ANDROGEN RECEPTOR DEFICIENCY, TESTICULAR FEMINIZATION SYNDROME, Androgen insensitivity syndrome.

## Similar variants {#similar}

Related AR variant pages (same residue, condition, or type): [AR c.1768+2T>C](/variant/ar-c-1768-plus-2t-c), [AR c.1769-11T>A](/variant/ar-c-1769-minus-11t-a), [AR c.2450-6C>G](/variant/ar-c-2450-minus-6c-g), [AR p.Ala588Pro](/variant/ar-p-ala588pro), [AR p.Ala597Thr](/variant/ar-p-ala597thr), [AR p.Ala688Val](/variant/ar-p-ala688val), [AR p.Ala766Thr](/variant/ar-p-ala766thr), [AR p.Ala871Val](/variant/ar-p-ala871val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2925892). 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.*