# NM_001032283.3(TMPO):c.87C>T (p.Ala29=)

https://sugi.bio/variant/tmpo-p-ala29

## Summary

**TMPO p.Ala29= (c.87C>T)** is classified **Benign/Likely benign** in TMPO (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-13). Rare (popmax 0.452%, afr); Associated with Loeys-Dietz syndrome 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs114074541 · 8 submitters · 1 linked condition · rare (popmax 0.452%, afr)

## For patients & families {#patients}

This is a change in the TMPO gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, 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.Ala29= |
| Coding change (HGVS c.) | c.87C>T |
| MANE Select transcript | [NM_001032283](https://www.ncbi.nlm.nih.gov/nuccore/NM_001032283) |
| dbSNP | [rs114074541](https://www.ncbi.nlm.nih.gov/snp/rs114074541/) |
| Variant type | single nucleotide variant |
| Location | chr12:98515954-98515954 (GRCh38) |
| ClinVar | [VCV44674](https://www.ncbi.nlm.nih.gov/clinvar/variation/44674/) |

**All HGVS expressions:** `LRG_443:g.5382C>T`, `LRG_443t1:c.87C>T`, `LRG_443t2:c.87C>T`, `NC_000012.11:g.98909732C>T`, `NC_000012.12:g.98515954C>T`, `NG_021393.1:g.5382C>T`, `NM_001032283.3:c.87C>T`, `NM_001032284.3:c.87C>T`, `NM_001307975.2:c.87C>T`, `NM_003276.2:c.87C>T`, `NR_027157.1:n.236+37G>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 0.266, GERP -0.102, phastCons 0.987 — weakly conserved position
- CADD: **PHRED 14.06**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.452%** (afr) · FAF95 0.412% · FAF99 0.397% · 339/75,040 in the highest group · 705/1,613,268 alleles overall — rare (popmax 0.452%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.771% | 130 |
| African / African-American (grpmax) | 0.452% | 221 |
| Remaining individuals (not grpmax-eligible) | 0.0864% | 1,157 |
| Admixed American | 0.0517% | 1,936 |
| Middle Eastern | 0.0495% | 2,020 |
| European (non-Finnish) | 0.00415% | 24,079 |
| South Asian | 0.0011% | 91,084 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **29** lies in the lem-like domain; a β-strand; 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.Ala29= falls in the lem-like domain.


### 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-13.

**Submitter consensus:** conflicting (5 Benign, 2 Likely benign).

**Submission history:** 8 submissions (2014–2026); 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 | 2026-01-13 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-03-18 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2014-08-12 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-01-28 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-24 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Loeys-Dietz syndrome 2, not specified, not provided, Malignant tumor of esophagus, AllHighlyPenetrant, none provided, TGFBR2-Related Loeys-Dietz Syndrome, AORTIC ANEURYSM, FAMILIAL THORACIC 3, MARFAN SYNDROME, TYPE II, Marfan syndrome, type 2 (formerly).

## Similar variants {#similar}

Related TMPO variant pages (same residue, condition, or type): [TMPO p.Ala29Thr](/variant/tmpo-p-ala29thr), [TMPO p.Ala29Ser](/variant/tmpo-p-ala29ser), [TMPO p.Ala29Val](/variant/tmpo-p-ala29val), [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).

### 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 44674). 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.*