# NM_014112.5(TRPS1):c.2700G>C (p.Arg900=)

https://sugi.bio/variant/trps1-p-arg900

## Summary

**TRPS1 p.Arg900= (c.2700G>C)** is classified **Uncertain significance** in TRPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-23). Absent from gnomAD v4.1; Associated with Trichorhinophalangeal syndrome, type III.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2130443039 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TRPS1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Trichorhinophalangeal syndrome, type III.

*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.Arg900= |
| Coding change (HGVS c.) | c.2700G>C |
| MANE Select transcript | [NM_014112](https://www.ncbi.nlm.nih.gov/nuccore/NM_014112) |
| dbSNP | [rs2130443039](https://www.ncbi.nlm.nih.gov/snp/rs2130443039/) |
| Variant type | single nucleotide variant |
| Location | chr8:115587001-115587001 (GRCh38) |
| ClinVar | [VCV1505084](https://www.ncbi.nlm.nih.gov/clinvar/variation/1505084/) |

**All HGVS expressions:** `NC_000008.10:g.116599228C>G`, `NC_000008.11:g.115587001C>G`, `NG_012383.3:g.87001G>C`, `NM_001282902.3:c.2673G>C`, `NM_001282903.3:c.2679G>C`, `NM_001330599.2:c.2661G>C`, `NM_014112.5:c.2700G>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.87) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.706, GERP 2.81, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.6**. 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 **0.87**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.57** (loss), gain 0.01 / loss 0.57. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-23 |

## Associated conditions {#conditions}

[Trichorhinophalangeal syndrome, type III](https://sugi.bio/atlas/disease/trichorhinophalangeal-syndrome-type-iii/), [trichorhinophalangeal syndrome type I](https://sugi.bio/atlas/disease/trichorhinophalangeal-syndrome-type-i/).

**Reported phenotype names (ClinVar):** Trichorhinophalangeal syndrome, type III, Trichorhinophalangeal dysplasia type I, SUGIO-KAJII SYNDROME, TRPS I, TRICHORHINOPHALANGEAL SYNDROME, TYPE I.

## Similar variants {#similar}

Related TRPS1 variant pages (same residue, condition, or type): [TRPS1 c.2097-2A>C](/variant/trps1-c-2097-minus-2a-c), [TRPS1 p.Ala932Thr](/variant/trps1-p-ala932thr), [TRPS1 p.Ala932Val](/variant/trps1-p-ala932val), [TRPS1 p.Arg257Ter](/variant/trps1-p-arg257ter), [TRPS1 p.Arg544Ter](/variant/trps1-p-arg544ter), [TRPS1 p.Arg624Ter](/variant/trps1-p-arg624ter), [TRPS1 p.Arg696Ter](/variant/trps1-p-arg696ter), [TRPS1 p.Arg921Gln](/variant/trps1-p-arg921gln).

### 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 1505084). 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.*