# NM_003292.3(TPR):c.1399C>A (p.Arg467=)

https://sugi.bio/variant/tpr-p-arg467

## Summary

**TPR p.Arg467= (c.1399C>A)** is classified **Benign/Likely benign** in TPR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-01). Rare (popmax 0.927%, nfe).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs114751429 · 2 submitters · rare (popmax 0.927%, nfe)

## For patients & families {#patients}

This is a change in the TPR gene that is classified as benign/likely benign — not considered disease-causing, 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 | [TPR](https://sugi.bio/atlas/gene/TPR/) |
| Protein change (HGVS p.) | p.Arg467= |
| Coding change (HGVS c.) | c.1399C>A |
| MANE Select transcript | [NM_003292](https://www.ncbi.nlm.nih.gov/nuccore/NM_003292) |
| dbSNP | [rs114751429](https://www.ncbi.nlm.nih.gov/snp/rs114751429/) |
| Variant type | single nucleotide variant |
| Location | chr1:186358641-186358641 (GRCh38) |
| ClinVar | [VCV770683](https://www.ncbi.nlm.nih.gov/clinvar/variation/770683/) |

**All HGVS expressions:** `NC_000001.10:g.186327773G>T`, `NC_000001.11:g.186358641G>T`, `NG_023284.1:g.21685C>A`, `NM_003292.3:c.1399C>A`

## 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 8.671, GERP 1.29, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.8**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.33 acceptor gain), 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 **0.927%** (nfe) · FAF95 0.912% · FAF99 0.906% · 10,920/1,178,356 in the highest group · 12,036/1,610,174 alleles overall — rare (popmax 0.927%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.927% | 108 |
| Remaining individuals (not grpmax-eligible) | 0.588% | 170 |
| Admixed American | 0.35% | 285 |
| Finnish (not grpmax-eligible) | 0.286% | 349 |
| Middle Eastern | 0.281% | 356 |
| South Asian | 0.25% | 400 |
| African / African-American | 0.135% | 740 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0475% | 2,107 |

*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}

**TPR** population constraint: LOEUF 0.203, pLI 1, missense-Z 3.9967. *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 **467** lies in the 'necessary for association to the npc' region.

AlphaFold model confidence (whole protein): pLDDT 61.60, 1% of residues very-high.

**4 experimental structure(s)** (PDB): [5TO5](https://www.rcsb.org/structure/5TO5), [5TO6](https://www.rcsb.org/structure/5TO6), [5TO7](https://www.rcsb.org/structure/5TO7), [5TVB](https://www.rcsb.org/structure/5TVB).

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

*Describes the biological roles of TPR (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:** TPR's established molecular role includes chromatin binding. p.Arg467= falls in the necessary for association to the npc region. In Reactome, TPR is annotated in disease pathway(s) including **Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)**, **HCMV Early Events**.

**Disease mechanism (Reactome):** TPR loss or alteration is curated in [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107), [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690), [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379).

### Pathways affected {#pathways}

TPR participates in **31 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| ⚕ [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379) | curated |
| ⚕ [NEP/NS2 Interacts with the Cellular Export Machinery](https://reactome.org/content/detail/R-HSA-168333) | curated |
| ⚕ [NS1 Mediated Effects on Host Pathways](https://reactome.org/content/detail/R-HSA-168276) | curated |
| ⚕ [Rev-mediated nuclear export of HIV RNA](https://reactome.org/content/detail/R-HSA-165054) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Transport of Ribonucleoproteins into the Host Nucleus](https://reactome.org/content/detail/R-HSA-168271) | curated |
| ⚕ [Viral Messenger RNA Synthesis](https://reactome.org/content/detail/R-HSA-168325) | curated |
| ⚕ [Vpr-mediated nuclear import of PICs](https://reactome.org/content/detail/R-HSA-180910) | curated |
| ⚕ [Nuclear import of Rev protein](https://reactome.org/content/detail/R-HSA-180746) | electronic |
| [IP3 and IP4 transport between cytosol and nucleus](https://reactome.org/content/detail/R-HSA-1855196) | curated |
| [IP6 and IP7 transport between cytosol and nucleus](https://reactome.org/content/detail/R-HSA-1855229) | curated |
| [IPs transport between nucleus and cytosol](https://reactome.org/content/detail/R-HSA-1855170) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Nuclear Pore Complex (NPC) Disassembly](https://reactome.org/content/detail/R-HSA-3301854) | curated |
| [Regulation of Glucokinase by Glucokinase Regulatory Protein](https://reactome.org/content/detail/R-HSA-170822) | curated |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [SUMOylation of RNA binding proteins](https://reactome.org/content/detail/R-HSA-4570464) | curated |
| [SUMOylation of SUMOylation proteins](https://reactome.org/content/detail/R-HSA-4085377) | curated |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [SUMOylation of ubiquitinylation proteins](https://reactome.org/content/detail/R-HSA-3232142) | curated |
| [Transport of Mature mRNA Derived from an Intronless Transcript](https://reactome.org/content/detail/R-HSA-159231) | curated |
| [Transport of Mature mRNA derived from an Intron-Containing Transcript](https://reactome.org/content/detail/R-HSA-159236) | curated |
| [Transport of the SLBP Dependant Mature mRNA](https://reactome.org/content/detail/R-HSA-159230) | curated |
| [Transport of the SLBP independent Mature mRNA](https://reactome.org/content/detail/R-HSA-159227) | curated |
| [snRNP Assembly](https://reactome.org/content/detail/R-HSA-191859) | curated |
| [tRNA processing in the nucleus](https://reactome.org/content/detail/R-HSA-6784531) | curated |
| [SUMOylation of DNA replication proteins](https://reactome.org/content/detail/R-HSA-4615885) | electronic |

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

**Molecular function:** chromatin binding, RNA binding, mRNA binding, tubulin binding, structural constituent of nuclear pore, heat shock protein binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, RNA import into nucleus, RNA export from nucleus, protein import into nucleus, nuclear pore organization, mitotic spindle assembly checkpoint signaling.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-01.

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

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-06-08 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-01 |

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

## Similar variants {#similar}

Related TPR variant pages (same residue, condition, or type): [TPR p.Arg467Gln](/variant/tpr-p-arg467gln), [TPR p.Thr1751Ala](/variant/tpr-p-thr1751ala), [TPR p.Arg1832His](/variant/tpr-p-arg1832his), [TPR p.Leu1314=](/variant/tpr-p-leu1314), [TPR p.Pro2168Ser](/variant/tpr-p-pro2168ser), [TPR p.Thr762=](/variant/tpr-p-thr762), [TPR c.2610+5G>A](/variant/tpr-c-2610-plus-5g-a), [TPR p.Ala1025Thr](/variant/tpr-p-ala1025thr).

### 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 770683). 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.*