# NM_003292.3(TPR):c.1336C>T (p.Arg446Cys)

https://sugi.bio/variant/tpr-p-arg446cys

## Summary

**TPR p.Arg446Cys (c.1336C>T)** is classified **Uncertain significance** in TPR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely benign (0.3271); Very rare (popmax 0.00272%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1266844942 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00272%, afr)

## For patients & families {#patients}

This is a change in the TPR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [TPR](https://sugi.bio/atlas/gene/TPR/) |
| Protein change (HGVS p.) | p.Arg446Cys |
| Coding change (HGVS c.) | c.1336C>T |
| MANE Select transcript | [NM_003292](https://www.ncbi.nlm.nih.gov/nuccore/NM_003292) |
| dbSNP | [rs1266844942](https://www.ncbi.nlm.nih.gov/snp/rs1266844942/) |
| Variant type | single nucleotide variant |
| Location | chr1:186359852-186359852 (GRCh38) |
| ClinVar | [VCV2364541](https://www.ncbi.nlm.nih.gov/clinvar/variation/2364541/) |

**All HGVS expressions:** `NC_000001.10:g.186328984G>A`, `NC_000001.11:g.186359852G>A`, `NG_023284.1:g.20474C>T`, `NM_003292.3:c.1336C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3271)
- REVEL 0.412 (indeterminate)
- SaProt LLR -10.207 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 11.853, GERP 1.76, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (186,357,555–186,375,028), spanning 17,473 bp. Chi-square p 0.043. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.26 donor 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 **0.00272%** (afr) · FAF95 0.00103% · FAF99 0.000832% · 2/73,632 in the highest group · 23/1,599,748 alleles overall — very rare (popmax 0.00272%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00272% | 36,816 |
| East Asian | 0.00224% | 44,566 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,884 |
| European (non-Finnish) | 0.00161% | 61,920 |

*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 **446** 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.Arg446Cys 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-17 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related TPR variant pages (same residue, condition, or type): [TPR p.Thr1751Ala](/variant/tpr-p-thr1751ala), [TPR p.Arg1832His](/variant/tpr-p-arg1832his), [TPR p.Arg467=](/variant/tpr-p-arg467), [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 2364541). 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.*