# NM_001388492.1(HTT):c.3128T>C (p.Leu1043Ser)

https://sugi.bio/variant/htt-p-leu1043ser

## Summary

**HTT p.Leu1043Ser (c.3128T>C)** is classified **Uncertain significance** in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1179); Ultra-rare (popmax 0.0167%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs945453962 · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0167%, amr)

## 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.

*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.Leu1043Ser |
| Coding change (HGVS c.) | c.3128T>C |
| MANE Select transcript | [NM_001388492](https://www.ncbi.nlm.nih.gov/nuccore/NM_001388492) |
| dbSNP | [rs945453962](https://www.ncbi.nlm.nih.gov/snp/rs945453962/) |
| Variant type | single nucleotide variant |
| Location | chr4:3145213-3145213 (GRCh38) |
| ClinVar | [VCV1386993](https://www.ncbi.nlm.nih.gov/clinvar/variation/1386993/) |

**All HGVS expressions:** `LRG_763:g.75539T>C`, `LRG_763t1:c.3134T>C`, `NC_000004.11:g.3146940T>C`, `NC_000004.12:g.3145213T>C`, `NG_009378.1:g.75539T>C`, `NM_001388492.1:c.3128T>C`, `NM_002111.8:c.3134T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1179)
- REVEL 0.224 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.398, GERP 0.553, phastCons 0.49 — highly conserved (differs from AlphaMissense)
- **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 23.8**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.25**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.25**.
- Population frequency (gnomAD v4.1): grpmax **0.0167%** (amr) · FAF95 0.009% · FAF99 0.00681% · 10/60,000 in the highest group · 12/1,612,172 alleles overall — ultra-rare (popmax 0.0167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0167% | 6,000 |
| European (non-Finnish) | 0.00017% | 589,147 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-22.

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

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-22 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-01 |

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

## Similar variants {#similar}

Related HTT variant pages (same residue, condition, or type): [HTT p.Leu1043Val](/variant/htt-p-leu1043val), [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).

### 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 1386993). 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.*