# NM_001388492.1(HTT):c.7498G>A (p.Val2500Ile)

https://sugi.bio/variant/htt-p-val2500ile

## Summary

**HTT p.Val2500Ile (c.7498G>A)** is classified **Uncertain significance** in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-04). AlphaMissense: likely benign (0.0958); Very rare (popmax 0.00268%, afr); Associated with Huntington disease.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs371399733 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the HTT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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/) |
| Protein change (HGVS p.) | p.Val2500Ile |
| Coding change (HGVS c.) | c.7498G>A |
| MANE Select transcript | [NM_001045](https://www.ncbi.nlm.nih.gov/nuccore/NM_001045) (variant reported on NM_001388492) |
| dbSNP | [rs371399733](https://www.ncbi.nlm.nih.gov/snp/rs371399733/) |
| Variant type | single nucleotide variant |
| Location | chr4:3223433-3223433 (GRCh38) |
| ClinVar | [VCV1355049](https://www.ncbi.nlm.nih.gov/clinvar/variation/1355049/) |

**All HGVS expressions:** `LRG_763:g.153759G>A`, `LRG_763t1:c.7504G>A`, `NC_000004.11:g.3225160G>A`, `NC_000004.12:g.3223433G>A`, `NG_009378.1:g.153759G>A`, `NM_001388492.1:c.7498G>A`, `NM_002111.5:c.7498G>A`, `NM_002111.8:c.7504G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0958)
- REVEL 0.178 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 9.788, GERP 1.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.8**. 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 **0.00268%** (afr) · FAF95 0.00157% · FAF99 0.00135% · 2/74,612 in the highest group · 31/1,604,380 alleles overall — very rare (popmax 0.00268%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00268% | 37,306 |
| European (non-Finnish) | 0.0023% | 43,528 |
| South Asian | 0.00222% | 44,948 |

*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, 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):

- **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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-24 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Huntington disease, not provided, HUNTINGTON CHOREA, Huntington's chorea, Huntington's disease, none provided.

## Similar variants {#similar}

Related HTT variant pages (same residue, condition, or type): [HTT p.Val2500=](/variant/htt-p-val2500), [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), [HTT c.7765+10G>A](/variant/htt-c-7765-plus-10g-a), [HTT p.Val1546=](/variant/htt-p-val1546), [HTT p.Val2617Met](/variant/htt-p-val2617met).

### 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 1355049). 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.*