# NM_000044.6(AR):c.1174C>T (p.Pro392Ser)

https://sugi.bio/variant/ar-p-pro392ser

## Summary

**AR p.Pro392Ser (c.1174C>T)** is classified **Conflicting classifications of pathogenicity** in AR (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0686); Low-frequency (popmax 2.49%, sas); Associated with partial androgen insensitivity syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201934623 · 16 submitters · 4 linked conditions · AlphaMissense likely benign · low-frequency (popmax 2.49%, sas)

## For patients & families {#patients}

This is a change in the AR gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 16 submitters, and is linked to partial androgen insensitivity syndrome.

*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) | All ages |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AR is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Partial androgen insensitivity syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Aplasia of the uterus — Very frequent (99-80%)
- Male infertility — Very frequent (99-80%)
- Aplasia of the ovary — Very frequent (99-80%)
- Elevated circulating luteinizing hormone level — Very frequent (99-80%)
- Increased serum testosterone level — Very frequent (99-80%)
- Increased antimullerian hormone level — Very frequent (99-80%)
- Male sexual dysfunction — Very frequent (99-80%)
- Hypospadias — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005692/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.Pro392Ser |
| Coding change (HGVS c.) | c.1174C>T |
| MANE Select transcript | [NM_000044](https://www.ncbi.nlm.nih.gov/nuccore/NM_000044) |
| dbSNP | [rs201934623](https://www.ncbi.nlm.nih.gov/snp/rs201934623/) |
| Variant type | single nucleotide variant |
| Location | chrX:67546320-67546320 (GRCh38) |
| ClinVar | [VCV216890](https://www.ncbi.nlm.nih.gov/clinvar/variation/216890/) |

**All HGVS expressions:** `LRG_1406:g.7289C>T`, `LRG_1406t1:c.1174C>T`, `NC_000023.10:g.66766162C>T`, `NC_000023.11:g.67546320C>T`, `NG_009014.2:g.7289C>T`, `NM_000044.6:c.1174C>T`, `NM_001011645.3:c.-610C>T`, `NM_001348061.1:c.1174C>T`, `NM_001348063.1:c.1174C>T`, `NM_001348064.1:c.1174C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0686)
- REVEL 0.766 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -6.306 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 2.143, GERP 0.339, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.38**. 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 **2.49%** (sas) · FAF95 2.38% · FAF99 2.34% · 1,377/55,219 in the highest group · 3,878/1,197,127 alleles overall — low-frequency (popmax 2.49%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 2.49% | 40 |
| Middle Eastern | 0.957% | 104 |
| Remaining individuals (not grpmax-eligible) | 0.344% | 290 |
| European (non-Finnish) | 0.239% | 418 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.234% | 427 |
| Admixed American | 0.193% | 517 |
| Finnish (not grpmax-eligible) | 0.0316% | 3,160 |
| African / African-American | 0.0279% | 3,580 |
| East Asian | 0.00605% | 16,523 |

*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 **392** lies in the 'interaction with znf318' region; a UniProt-annotated variant site (in ais); the 'modulating' 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.Pro392Ser 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (8 Likely benign, 4 Benign, 2 Pathogenic, 2 Uncertain significance).

**Submission history:** 16 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Biochemistry Laboratory, Health Services Laboratory | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-20 |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2024-02-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2016-09-22 |
| Clinical Genetics and Genomics, Karolinska University Hospital | Pathogenic | flagged submission | clinical testing | 2014-08-20 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-04 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-07-02 |
| UCLA Clinical Genomics Center, UCLA | Pathogenic | criteria provided, single submitter | clinical testing | 2014-07-01 |
| Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Uncertain significance | no assertion criteria provided | clinical testing | 2018-01-31 |
| Pars Genome Lab | Benign | criteria provided, single submitter | clinical testing | 2022-02-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-30 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |

## Associated conditions {#conditions}

[partial androgen insensitivity syndrome](https://sugi.bio/atlas/disease/partial-androgen-insensitivity-syndrome/), [hypospadias 1, X-linked](https://sugi.bio/atlas/disease/hypospadias-1-x-linked/), [Kennedy disease](https://sugi.bio/atlas/disease/kennedy-disease/), [androgen insensitivity syndrome](https://sugi.bio/atlas/disease/androgen-insensitivity-syndrome/).

**Reported phenotype names (ClinVar):** Partial androgen insensitivity syndrome, not specified, Hypospadias 1, X-linked, Androgen resistance syndrome, not provided, Kennedy disease, AR-related disorder, AR-related condition, ANDROGEN INSENSITIVITY, PARTIAL, WITH OR WITHOUT BREAST CANCER, Reifenstein syndrome.

## Similar variants {#similar}

Related AR variant pages (same residue, condition, or type): [AR p.Pro392Arg](/variant/ar-p-pro392arg), [AR p.Pro392Leu](/variant/ar-p-pro392leu), [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 216890). 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.*