# NM_001388492.1(HTT):c.2414C>T (p.Ala805Val)

https://sugi.bio/variant/htt-p-ala805val

## Summary

**HTT p.Ala805Val (c.2414C>T)** is classified **Conflicting classifications of pathogenicity** in HTT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-02). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0267%, eas).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0267%, eas)

## For patients & families {#patients}

This is a change in the HTT gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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.*

**Support & next steps:** [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.Ala805Val |
| Coding change (HGVS c.) | c.2414C>T |
| MANE Select transcript | [NM_001388492](https://www.ncbi.nlm.nih.gov/nuccore/NM_001388492) |
| Variant type | single nucleotide variant |
| Location | chr4:3132832-3132832 (GRCh38) |
| ClinVar | [VCV3361821](https://www.ncbi.nlm.nih.gov/clinvar/variation/3361821/) |

**All HGVS expressions:** `LRG_763:g.63158C>T`, `LRG_763t1:c.2420C>T`, `NC_000004.11:g.3134559C>T`, `NC_000004.12:g.3132832C>T`, `NG_009378.1:g.63158C>T`, `NM_001388492.1:c.2414C>T`, `NM_002111.8:c.2420C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0693)
- REVEL 0.284 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -8.459, GERP -3.34 — fast-evolving / accelerated position
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 0.444**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.37 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (eas) · FAF95 0.0154% · FAF99 0.0121% · 12/44,882 in the highest group · 34/1,613,890 alleles overall — ultra-rare (popmax 0.0267%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0267% | 3,740 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,416 |
| South Asian | 0.00329% | 30,355 |
| African / African-American | 0.00267% | 37,508 |
| European (non-Finnish) | 0.000848% | 117,981 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-02.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-02 |

**Reported phenotype names (ClinVar):** not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related HTT variant pages (same residue, condition, or type): [HTT c.889+6G>T](/variant/htt-c-889-plus-6g-t), [HTT p.Ala2739Thr](/variant/htt-p-ala2739thr), [HTT p.Arg1654Trp](/variant/htt-p-arg1654trp), [HTT p.Arg1945Trp](/variant/htt-p-arg1945trp), [HTT p.Asp1157Gly](/variant/htt-p-asp1157gly), [HTT p.Asp920Asn](/variant/htt-p-asp920asn), [HTT p.Glu449Ala](/variant/htt-p-glu449ala), [HTT p.Gly2084Arg](/variant/htt-p-gly2084arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3361821). 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.*