# NM_014112.5(TRPS1):c.3203dup (p.Ser1069fs)

https://sugi.bio/variant/trps1-p-ser1069fs

## Summary

**TRPS1 p.Ser1069fs (c.3203dup)** is classified **Pathogenic** in TRPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-26). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1812870694 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TRPS1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [TRPS1](https://sugi.bio/atlas/gene/TRPS1/) |
| Protein change (HGVS p.) | p.Ser1069fs |
| Coding change (HGVS c.) | c.3203dup |
| MANE Select transcript | [NM_014112](https://www.ncbi.nlm.nih.gov/nuccore/NM_014112) |
| dbSNP | [rs1812870694](https://www.ncbi.nlm.nih.gov/snp/rs1812870694/) |
| Variant type | Duplication |
| Location | chr8:115414704-115414705 (GRCh38) |
| ClinVar | [VCV986161](https://www.ncbi.nlm.nih.gov/clinvar/variation/986161/) |

**All HGVS expressions:** `NC_000008.10:g.116426933dup`, `NC_000008.11:g.115414705dup`, `NG_012383.3:g.259297dup`, `NM_001282902.3:c.3176dup`, `NM_001282903.3:c.3182dup`, `NM_001330599.2:c.3164dup`, `NM_014112.5:c.3203dup`

## Computational & population evidence {#evidence}

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

- **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 -4.061, GERP -3.74 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.114, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**TRPS1** population constraint: LOEUF 0.114, pLI 1, missense-Z 2.597; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **1069** lies in the 'mediates interaction with rnf4' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 49.12, 3% of residues very-high.

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

*Describes the biological roles of TRPS1 (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:** TRPS1's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Ser1069fs falls in the mediates interaction with rnf4 region.


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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, protein domain specific binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, skeletal system development.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-01-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related TRPS1 variant pages (same residue, condition, or type): [TRPS1 p.His576fs](/variant/trps1-p-his576fs), [TRPS1 p.Leu1177fs](/variant/trps1-p-leu1177fs), [TRPS1 p.Ser1069Thr](/variant/trps1-p-ser1069thr), [TRPS1 p.Arg696Ter](/variant/trps1-p-arg696ter), [TRPS1 p.Ala196Val](/variant/trps1-p-ala196val), [TRPS1 p.Ala848Thr](/variant/trps1-p-ala848thr), [TRPS1 p.Arg1125Gln](/variant/trps1-p-arg1125gln), [TRPS1 p.Asn738Ser](/variant/trps1-p-asn738ser).

### 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 986161). 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.*