# NM_000044.6(AR):c.2324G>A (p.Arg775His)

https://sugi.bio/variant/ar-p-arg775his

## Summary

**AR p.Arg775His (c.2324G>A)** is classified **Pathogenic** in AR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-14). AlphaMissense: likely pathogenic (0.9877); Absent from gnomAD v4.1; Associated with Kennedy disease.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs137852572 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AR gene that is considered disease-causing, submitted by 4 submitters, 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 13 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.Arg775His |
| Coding change (HGVS c.) | c.2324G>A |
| MANE Select transcript | [NM_024417](https://www.ncbi.nlm.nih.gov/nuccore/NM_024417) (variant reported on NM_000044) |
| dbSNP | [rs137852572](https://www.ncbi.nlm.nih.gov/snp/rs137852572/) |
| Variant type | single nucleotide variant |
| Location | chrX:67721838-67721838 (GRCh38) |
| ClinVar | [VCV9819](https://www.ncbi.nlm.nih.gov/clinvar/variation/9819/) |

**All HGVS expressions:** `LRG_1406:g.182807G>A`, `LRG_1406t1:c.2324G>A`, `NC_000023.10:g.66941680G>A`, `NC_000023.11:g.67721838G>A`, `NG_009014.2:g.182807G>A`, `NM_000044.6:c.2324G>A`, `NM_001011645.3:c.728G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9877) — concordant with the pathogenic call
- REVEL 0.951 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.235 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.715, GERP 1.43, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 2%** most-pathogenic-predicted substitutions in AR (of 2,849 modeled).
- CADD: **PHRED 31.0**. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**AR** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **Kennedy disease** — Definitive (XL)
- **FDXR-related optic atrophy mitochondrial dysfunction syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.66, 88% of residues very-high.

## 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 ferredoxin-NADP+ reductase activity. In Reactome, AR is annotated in disease pathway(s) including **Defective CYP11A1 causes AICSR**.

**Disease mechanism (Reactome):** AR loss or alteration is curated in [Defective CYP11A1 causes AICSR](https://reactome.org/content/detail/R-HSA-5579026).

### Pathways affected {#pathways}

AR participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CYP11A1 causes AICSR](https://reactome.org/content/detail/R-HSA-5579026) | curated |
| [Electron transport from NADPH to Ferredoxin](https://reactome.org/content/detail/R-HSA-2395516) | curated |
| [Endogenous sterols](https://reactome.org/content/detail/R-HSA-211976) | curated |
| [Pregnenolone biosynthesis](https://reactome.org/content/detail/R-HSA-196108) | curated |

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

**Molecular function:** ferredoxin-NADP+ reductase activity.

**Biological process:** ubiquinone biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-14.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (1992–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1992-07-01 |
| Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Pathogenic | no assertion criteria provided | clinical testing | 2023-07-20 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2020-02-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-14 |

## 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, not provided, KENNEDY SPINAL AND BULBAR MUSCULAR ATROPHY, SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1, Spinal and Bulbar Muscular Atrophy, Androgen insensitivity, complete, DIHYDROTESTOSTERONE RECEPTOR DEFICIENCY, Androgen insensitivity, Androgen insensitivity syndrome.

## Same-residue context {#hotspot}

Residue **775** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AR p.Arg775Cys](/variant/ar-p-arg775cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AR variant pages (same residue, condition, or type): [AR p.Arg775Cys](/variant/ar-p-arg775cys), [AR p.Arg775Gly](/variant/ar-p-arg775gly), [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).

### 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 9819). 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.*