# NM_001267550.2(TTN):c.135G>T (p.Val45=)

https://sugi.bio/variant/ttn-p-val45

## Summary

**TTN p.Val45= (c.135G>T)** is classified **Likely benign** in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-23). Very rare (popmax 0.00169%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Single submitter · rsID rs1189066391 · 1 submitter · 1 linked condition · very rare (popmax 0.00169%, nfe)

## For patients & families {#patients}

This is a change in the TTN gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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 | [TTN](https://sugi.bio/atlas/gene/TTN/) |
| Protein change (HGVS p.) | p.Val45= |
| Coding change (HGVS c.) | c.135G>T |
| MANE Select transcript | [NM_001267550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001267550) |
| dbSNP | [rs1189066391](https://www.ncbi.nlm.nih.gov/snp/rs1189066391/) |
| Variant type | single nucleotide variant |
| Location | chr2:178802298-178802298 (GRCh38) |
| ClinVar | [VCV1770812](https://www.ncbi.nlm.nih.gov/clinvar/variation/1770812/) |

**All HGVS expressions:** `LRG_391:g.33505G>T`, `LRG_391t1:c.135G>T`, `LRG_391t2:c.135G>T`, `NC_000002.11:g.179667025C>A`, `NC_000002.12:g.178802298C>A`, `NG_011618.3:g.33505G>T`, `NM_001256850.1:c.135G>T`, `NM_001267550.2:c.135G>T`, `NM_003319.4:c.135G>T`, `NM_133378.4:c.135G>T`, `NM_133379.5:c.135G>T`, `NM_133432.3:c.135G>T`, `NM_133437.4:c.135G>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 -0.439, GERP -3.88, phastCons 0.015 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.493**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.35 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 (gnomAD v4.1): grpmax **0.00169%** (nfe) · FAF95 0.00111% · FAF99 0.0009% · 20/1,180,014 in the highest group · 20/1,614,000 alleles overall — very rare (popmax 0.00169%, nfe).

*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}

**TTN** population constraint: LOEUF 0.479, pLI 1.3925e-89, missense-Z 7.0514; ClinGen dosage — haploinsufficiency 2/3, 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 1G** — Definitive (AD)
- **TTN-related myopathy** — Definitive (AR)
- **arrhythmogenic right ventricular cardiomyopathy** — Disputed (AD)
- **myopathy, myofibrillar, 9, with early respiratory failure** — Definitive (AD)

## Protein context {#protein}

Residue **45** lies in the ig-like 1 domain; a β-strand.

**64 experimental structure(s)** (PDB): [1BPV](https://www.rcsb.org/structure/1BPV), [1G1C](https://www.rcsb.org/structure/1G1C), [1NCT](https://www.rcsb.org/structure/1NCT), [1NCU](https://www.rcsb.org/structure/1NCU), [1TIT](https://www.rcsb.org/structure/1TIT), [1TIU](https://www.rcsb.org/structure/1TIU) — incl. mutant structure 2RQ8.

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

*Describes the biological roles of TTN (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:** TTN's established molecular role includes protease binding. p.Val45= falls in the ig-like 1 domain.


### Pathways affected {#pathways}

TTN participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |

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

**Molecular function:** protease binding, protein serine/threonine kinase activity, protein tyrosine kinase activity, calcium ion binding, calmodulin binding, structural constituent of muscle.

**Biological process:** cardiac muscle hypertrophy, mitotic chromosome condensation, positive regulation of gene expression, skeletal muscle thin filament assembly, skeletal muscle myosin thick filament assembly, detection of muscle stretch.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-23.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-23 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Same-residue context {#hotspot}

Residue **45** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TTN p.Val45fs](/variant/ttn-p-val45fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TTN variant pages (same residue, condition, or type): [TTN p.Val45fs](/variant/ttn-p-val45fs), [TTN p.Val45Leu](/variant/ttn-p-val45leu), [TTN c.107377+1G>C](/variant/ttn-c-107377-plus-1g-c), [TTN c.54190+1G>A](/variant/ttn-c-54190-plus-1g-a), [TTN c.54811+1G>A](/variant/ttn-c-54811-plus-1g-a), [TTN c.57112-1G>A](/variant/ttn-c-57112-minus-1g-a), [TTN c.58732+2T>C](/variant/ttn-c-58732-plus-2t-c), [TTN c.95723-2A>C](/variant/ttn-c-95723-minus-2a-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 1770812). 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.*