# NM_001032283.3(TMPO):c.284C>T (p.Ala95Val)

https://sugi.bio/variant/tmpo-p-ala95val

## Summary

**TMPO p.Ala95Val (c.284C>T)** is classified **Uncertain significance** in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-22). AlphaMissense: likely pathogenic (0.8267); Absent from gnomAD v4.1; Associated with Loeys-Dietz syndrome 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1565808154 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TMPO gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Loeys-Dietz syndrome 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010586/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TMPO](https://sugi.bio/atlas/gene/TMPO/) |
| Protein change (HGVS p.) | p.Ala95Val |
| Coding change (HGVS c.) | c.284C>T |
| MANE Select transcript | [NM_001032283](https://www.ncbi.nlm.nih.gov/nuccore/NM_001032283) |
| dbSNP | [rs1565808154](https://www.ncbi.nlm.nih.gov/snp/rs1565808154/) |
| Variant type | single nucleotide variant |
| Location | chr12:98527890-98527890 (GRCh38) |
| ClinVar | [VCV2748838](https://www.ncbi.nlm.nih.gov/clinvar/variation/2748838/) |

**All HGVS expressions:** `LRG_443:g.17318C>T`, `LRG_443t1:c.284C>T`, `LRG_443t2:c.284C>T`, `NC_000012.11:g.98921668C>T`, `NC_000012.12:g.98527890C>T`, `NG_021393.1:g.17318C>T`, `NM_001032283.3:c.284C>T`, `NM_001032284.3:c.284C>T`, `NM_001307975.2:c.284C>T`, `NM_003276.2:c.284C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8267)
- REVEL 0.172 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -6.784 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 7.617, GERP 2.15, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.7**. 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 1.01** across the covering region of the MANE Select transcript (98,515,868–98,544,296), spanning 28,428 bp. Chi-square p 0.89. 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 (C>A, Δ0.23 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: **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}

**TMPO** population constraint: LOEUF 0.736, pLI 0.0039603, missense-Z 0.85831. *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):

- **hypertrophic cardiomyopathy** — Limited (AD)
- **obsolete familial isolated dilated cardiomyopathy** — Refuted (AD)

## Protein context {#protein}

Residue **95** lies in the 'disordered' region; the 'linker' region; the 'nucleoplasmic' region.

AlphaFold model confidence (whole protein): pLDDT 60.49, 19% of residues very-high.

**14 experimental structure(s)** (PDB): [1GJJ](https://www.rcsb.org/structure/1GJJ), [1H9E](https://www.rcsb.org/structure/1H9E), [1H9F](https://www.rcsb.org/structure/1H9F), [8FN7](https://www.rcsb.org/structure/8FN7), [8FND](https://www.rcsb.org/structure/8FND), [8FNG](https://www.rcsb.org/structure/8FNG).

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

*Describes the biological roles of TMPO (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:** TMPO's established molecular role includes cadherin binding. p.Ala95Val falls in the disordered region.


### Pathways affected {#pathways}

TMPO participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOF GTPase cycle](https://reactome.org/content/detail/R-HSA-9035034) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [Depolymerization of the Nuclear Lamina](https://reactome.org/content/detail/R-HSA-4419969) | other |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | other |
| [Nuclear Envelope Breakdown](https://reactome.org/content/detail/R-HSA-2980766) | other |

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

**Molecular function:** cadherin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-22.

**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 | 2023-10-22 |

## Associated conditions {#conditions}

[Loeys-Dietz syndrome 2](https://sugi.bio/atlas/disease/loeys-dietz-syndrome-2/).

**Reported phenotype names (ClinVar):** Loeys-Dietz syndrome 2, Marfan Syndrome type 2, Marfan like connective tissue disorder, MFS 2, AORTIC ANEURYSM, FAMILIAL THORACIC 3, MARFAN SYNDROME, TYPE II, TGFBR2-Related Loeys-Dietz Syndrome, Marfan syndrome, type 2 (formerly).

## Similar variants {#similar}

Related TMPO variant pages (same residue, condition, or type): [TMPO p.Ala95Asp](/variant/tmpo-p-ala95asp), [TMPO c.565+1005A>G](/variant/tmpo-c-565-plus-1005a-g), [TMPO c.565+1009T>C](/variant/tmpo-c-565-plus-1009t-c), [TMPO c.565+1012A>C](/variant/tmpo-c-565-plus-1012a-c), [TMPO c.565+1017A>G](/variant/tmpo-c-565-plus-1017a-g), [TMPO c.565+1026A>G](/variant/tmpo-c-565-plus-1026a-g), [TMPO c.565+1029G>T](/variant/tmpo-c-565-plus-1029g-t), [TMPO c.565+1048G>C](/variant/tmpo-c-565-plus-1048g-c).

### 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 2748838). 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.*