# NM_002111.8(HTT):c.52CAG[?_25]

https://sugi.bio/variant/htt-c-52cag-25

## Summary

**HTT c.52CAG[?_25]** is classified **Benign** in HTT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2010-04-22). Associated with Huntington disease.

**At a glance:** Benign · review: No assertion criteria · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the HTT gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to Huntington 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) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-9 / 100 000 (Greece) |
| Clinical trials | 273 registered for this condition — see ClinicalTrials.gov |

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

- Mental deterioration — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Chorea — Very frequent (99-80%)
- Gait disturbance — Frequent (79-30%)
- Abnormality of eye movement — Frequent (79-30%)
- Agitation — Frequent (79-30%)
- Depression — Frequent (79-30%)
- Aggressive behavior — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006677/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HTT](https://sugi.bio/atlas/gene/HTT/) |
| Coding change (HGVS c.) | c.52CAG[?_25] |
| MANE Select transcript | [NM_001388492](https://www.ncbi.nlm.nih.gov/nuccore/NM_001388492) (variant reported on NM_002111) |
| Variant type | Microsatellite |
| Location | chr4:3074877-3074879 (GRCh38) |
| ClinVar | [VCV21303](https://www.ncbi.nlm.nih.gov/clinvar/variation/21303/) |

**All HGVS expressions:** `LRG_763:g.5197CAG[?_25]`, `LRG_763t1:c.52CAG[?_25]`, `NC_000004.11:g.3076604CAG[?_25]`, `NC_000004.12:g.3074877CAG[?_25]`, `NG_009378.1:g.5197CAG[?_25]`, `NM_002111.8:c.52CAG[?_25]`

## Computational & population evidence {#evidence}

- Repeat context: **simple_repeat** ((CAG)n, CAG). The alignment of this microsatellite is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*

*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}

**HTT** population constraint: ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **Huntington disease** — Definitive (AD)
- **autism spectrum disorder** — Disputed (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.38, 75% of residues very-high.

**30 experimental structure(s)** (PDB): [5I6X](https://www.rcsb.org/structure/5I6X), [5I6Z](https://www.rcsb.org/structure/5I6Z), [5I71](https://www.rcsb.org/structure/5I71), [5I73](https://www.rcsb.org/structure/5I73), [5I74](https://www.rcsb.org/structure/5I74), [5I75](https://www.rcsb.org/structure/5I75).

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

*Describes the biological roles of HTT (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:** HTT's established molecular role includes integrin binding.


### Pathways affected {#pathways}

HTT participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [SLC-mediated transport of neurotransmitters](https://reactome.org/content/detail/R-HSA-442660) | curated |
| [Serotonin clearance from the synaptic cleft](https://reactome.org/content/detail/R-HSA-380615) | curated |

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

**Molecular function:** integrin binding, serotonin:sodium:chloride symporter activity, monoamine transmembrane transporter activity, antiporter activity, sodium ion binding, serotonin binding.

**Biological process:** response to toxic substance, obsolete monoamine transport, serotonin uptake, regulation of thalamus size.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2010-04-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | Benign | no assertion criteria provided | curation | 2010-04-22 |

## Associated conditions {#conditions}

[Huntington disease](https://sugi.bio/atlas/disease/huntington-disease/).

**Reported phenotype names (ClinVar):** Huntington disease, Huntington's chorea, Huntington's disease, HUNTINGTON CHOREA.

## Similar variants {#similar}

Related HTT variant pages (same residue, condition, or type): [HTT c.52CAG[55_59]](/variant/htt-c-52cag-55-59), [HTT p.Gln18_Gln38dup](/variant/htt-p-gln18-gln38dup), [HTT p.Gln36_Gln38dup](/variant/htt-p-gln36-gln38dup), [HTT p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln](/variant/htt-p-gln38-pro39insglnglnglnglnglnglnglnglnglngln), [HTT p.Asp920Asn](/variant/htt-p-asp920asn), [HTT p.Gly2084Arg](/variant/htt-p-gly2084arg), [HTT p.Gly2968Asp](/variant/htt-p-gly2968asp), [HTT p.Pro703Leu](/variant/htt-p-pro703leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 21303). 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.*