# NM_001032283.3(TMPO):c.248C>T (p.Ala83Val)

https://sugi.bio/variant/tmpo-p-ala83val

## Summary

**TMPO p.Ala83Val (c.248C>T)** is classified **Uncertain significance** in TMPO (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-14). AlphaMissense: likely benign (0.0861); Very rare (popmax 0.00979%, sas); Associated with Loeys-Dietz syndrome 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs730880228 · 5 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00979%, sas)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## 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 5 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.Ala83Val |
| Coding change (HGVS c.) | c.248C>T |
| MANE Select transcript | [NM_001032283](https://www.ncbi.nlm.nih.gov/nuccore/NM_001032283) |
| dbSNP | [rs730880228](https://www.ncbi.nlm.nih.gov/snp/rs730880228/) |
| Variant type | single nucleotide variant |
| Location | chr12:98516115-98516115 (GRCh38) |
| ClinVar | [VCV180547](https://www.ncbi.nlm.nih.gov/clinvar/variation/180547/) |

**All HGVS expressions:** `LRG_443:g.5543C>T`, `LRG_443t2:c.248C>T`, `NC_000012.11:g.98909893C>T`, `NC_000012.12:g.98516115C>T`, `NG_021393.1:g.5543C>T`, `NM_001032283.3:c.248C>T`, `NM_001032284.3:c.248C>T`, `NM_001307975.2:c.248C>T`, `NM_003276.2:c.248C>T`, `NR_027157.1:n.112G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0861)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.635 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.079, GERP 0.412, phastCons 0.011 — weakly conserved position
- CADD: **PHRED 15.27**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00979%** (sas) · FAF95 0.0048% · FAF99 0.00353% · 8/81,756 in the highest group · 24/1,527,602 alleles overall — very rare (popmax 0.00979%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00979% | 10,220 |
| Remaining individuals (not grpmax-eligible) | 0.00169% | 59,260 |
| European (non-Finnish) | 0.00131% | 76,395 |

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-14.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-05 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-14 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-19 |

## 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 provided, not specified, AllHighlyPenetrant, none provided, TGFBR2-Related Loeys-Dietz Syndrome, Marfan syndrome, type 2 (formerly), Marfan Syndrome type 2, Marfan like connective tissue disorder, MFS 2.

### 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 180547). 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.*