# NM_001388492.1(HTT):c.2085del (p.Gly697fs)

https://sugi.bio/variant/htt-p-gly697fs

## Summary

**HTT p.Gly697fs (c.2085del)** is classified **Pathogenic** in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). Very rare (popmax 0.000424%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs745583559 · 1 submitter · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the HTT gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.Gly697fs |
| Coding change (HGVS c.) | c.2085del |
| MANE Select transcript | [NM_001388492](https://www.ncbi.nlm.nih.gov/nuccore/NM_001388492) |
| dbSNP | [rs745583559](https://www.ncbi.nlm.nih.gov/snp/rs745583559/) |
| Variant type | Deletion |
| Location | chr4:3131384-3131384 (GRCh38) |
| ClinVar | [VCV1464611](https://www.ncbi.nlm.nih.gov/clinvar/variation/1464611/) |

**All HGVS expressions:** `LRG_763:g.61710del`, `LRG_763t1:c.2091del`, `NC_000004.11:g.3133111del`, `NC_000004.12:g.3131384del`, `NG_009378.1:g.61710del`, `NM_001388492.1:c.2085del`, `NM_002111.8:c.2091del`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.261, GERP -0.068, phastCons 0.998 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,062 in the highest group · 6/1,612,902 alleles overall — very rare (popmax 0.000424%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,464 |
| European (non-Finnish) (grpmax) | 0.000424% | 235,812 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-19 |

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

## Similar variants {#similar}

Related HTT variant pages (same residue, condition, or type): [HTT c.5369-9del](/variant/htt-c-5369-minus-9del), [HTT p.Gln33fs](/variant/htt-p-gln33fs), [HTT p.Ser1941fs](/variant/htt-p-ser1941fs), [HTT c.2099-21_2099-13del](/variant/htt-c-2099-minus-21-2099-minus-13del), [HTT c.747+4del](/variant/htt-c-747-plus-4del), [HTT c.7766-13_7766-8del](/variant/htt-c-7766-minus-13-7766-minus-8del), [SLC6A4 c.*2091del](/variant/slc6a4-c-star-2091del), [HTT c.264-17_264-14del](/variant/htt-c-264-minus-17-264-minus-14del).

### 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 2026-10-14); 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 1464611). 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.*