# NM_001276345.2(TNNT2):c.450C>T (p.Ile150=)

https://sugi.bio/variant/tnnt2-p-ile150

## Summary

**TNNT2 p.Ile150= (c.450C>T)** is classified **Likely benign** in TNNT2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-12-07). Very rare (popmax 0.00525%, nfe); Associated with cardiomyopathy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs200604266 · 12 submitters · 4 linked conditions · very rare (popmax 0.00525%, nfe)

## For patients & families {#patients}

This is a change in the TNNT2 gene that is classified as likely benign — not considered disease-causing, submitted by 12 submitters, and is linked to cardiomyopathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 333 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TNNT2](https://sugi.bio/atlas/gene/TNNT2/) |
| Protein change (HGVS p.) | p.Ile150= |
| Coding change (HGVS c.) | c.450C>T |
| MANE Select transcript | [NM_001276345](https://www.ncbi.nlm.nih.gov/nuccore/NM_001276345) |
| dbSNP | [rs200604266](https://www.ncbi.nlm.nih.gov/snp/rs200604266/) |
| Variant type | single nucleotide variant |
| Location | chr1:201364337-201364337 (GRCh38) |
| ClinVar | [VCV516901](https://www.ncbi.nlm.nih.gov/clinvar/variation/516901/) |

**All HGVS expressions:** `LRG_431:g.18341C>T`, `LRG_431t1:c.450C>T`, `NC_000001.10:g.201333465G>A`, `NC_000001.11:g.201364337G>A`, `NG_007556.1:g.18341C>T`, `NM_000364.4:c.450C>T`, `NM_001001430.3:c.420C>T`, `NM_001001431.3:c.420C>T`, `NM_001001432.3:c.405C>T`, `NM_001276345.2:c.450C>T`, `NM_001276346.2:c.330C>T`, `NM_001276347.2:c.420C>T`

## 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 2.273, GERP -3.01, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.751**. 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 **0.00525%** (nfe) · FAF95 0.00418% · FAF99 0.0038% · 62/1,179,986 in the highest group · 66/1,613,306 alleles overall — very rare (popmax 0.00525%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00525% | 19,032 |
| Admixed American | 0.00333% | 30,012 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |
| African / African-American | 0.00133% | 75,056 |

*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}

**TNNT2** population constraint: LOEUF 0.683, pLI 0.0002824, missense-Z 2.1516; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **dilated cardiomyopathy 1D** — Definitive (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **150** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 78.93, 44% of residues very-high.

**25 experimental structure(s)** (PDB): [1J1D](https://www.rcsb.org/structure/1J1D), [1J1E](https://www.rcsb.org/structure/1J1E), [4Y99](https://www.rcsb.org/structure/4Y99), [6KN7](https://www.rcsb.org/structure/6KN7), [6KN8](https://www.rcsb.org/structure/6KN8), [7UTI](https://www.rcsb.org/structure/7UTI) — incl. mutant structure 9MO9.

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

*Describes the biological roles of TNNT2 (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:** TNNT2's established molecular role includes actin binding. p.Ile150= falls in the disordered region.


### Pathways affected {#pathways}

TNNT2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |

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

**Molecular function:** actin binding, tropomyosin binding, troponin C binding, troponin I binding, identical protein binding.

**Biological process:** regulation of heart contraction, muscle filament sliding, negative regulation of ATP-dependent activity, positive regulation of ATP-dependent activity, response to calcium ion, ventricular cardiac muscle tissue morphogenesis.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-07.

**Submitter consensus:** conflicting (11 Likely benign, 2 Benign, 1 Likely Benign).

**Submission history:** 14 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2019-01-06 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-11-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-07 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-22 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-11 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-10 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-11-28 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-16 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [hypertrophic cardiomyopathy 2](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-2/), [dilated cardiomyopathy 1D](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1d/), [cardiomyopathy, familial restrictive, 3](https://sugi.bio/atlas/disease/cardiomyopathy-familial-restrictive-3/).

**Reported phenotype names (ClinVar):** Cardiomyopathy, not specified, Cardiomyopathy, familial restrictive, 3, Dilated cardiomyopathy 1D, Hypertrophic cardiomyopathy 2, not provided, Cardiovascular phenotype, none provided, Cardiomyopathies, AllHighlyPenetrant.

## Similar variants {#similar}

Related TNNT2 variant pages (same residue, condition, or type): [TNNT2 p.Ile150Val](/variant/tnnt2-p-ile150val), [TNNT2 p.Ile150Asn](/variant/tnnt2-p-ile150asn), [TNNT2 p.Ile150Leu](/variant/tnnt2-p-ile150leu), [TNNT2 c.851+1G>A](/variant/tnnt2-c-851-plus-1g-a), [TNNT2 p.Arg104His](/variant/tnnt2-p-arg104his), [TNNT2 p.Trp297Ter](/variant/tnnt2-p-trp297ter), [TNNT2 p.Arg296Cys](/variant/tnnt2-p-arg296cys), [TNNT2 p.Arg288Cys](/variant/tnnt2-p-arg288cys).

### 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 516901). 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.*