# NM_001267550.2(TTN):c.156C>T (p.Pro52=)

https://sugi.bio/variant/ttn-p-pro52

## Summary

**TTN p.Pro52= (c.156C>T)** is classified **Conflicting classifications of pathogenicity** in TTN (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-01). Rare (popmax 0.182%, mid); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs72647842 · 11 submitters · 4 linked conditions · rare (popmax 0.182%, mid)

## For patients & families {#patients}

This is a change in the TTN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 11 submitters, 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.Pro52= |
| Coding change (HGVS c.) | c.156C>T |
| MANE Select transcript | [NM_001267550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001267550) |
| dbSNP | [rs72647842](https://www.ncbi.nlm.nih.gov/snp/rs72647842/) |
| Variant type | single nucleotide variant |
| Location | chr2:178802277-178802277 (GRCh38) |
| ClinVar | [VCV166360](https://www.ncbi.nlm.nih.gov/clinvar/variation/166360/) |

**All HGVS expressions:** `LRG_391:g.33526C>T`, `LRG_391t1:c.156C>T`, `NC_000002.11:g.179667004G>A`, `NC_000002.12:g.178802277G>A`, `NG_011618.3:g.33526C>T`, `NM_001256850.1:c.156C>T`, `NM_001267550.2:c.156C>T`, `NM_003319.4:c.156C>T`, `NM_133378.4:c.156C>T`, `NM_133379.5:c.156C>T`, `NM_133432.3:c.156C>T`, `NM_133437.4:c.156C>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 8.663, GERP 2.02, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.07**. 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 (G>T, Δ0.64 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 **0.182%** (mid) · FAF95 0.102% · FAF99 0.0787% · 11/6,060 in the highest group · 272/1,614,120 alleles overall — rare (popmax 0.182%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.182% | 551 |
| African / African-American | 0.0853% | 1,172 |
| Remaining individuals (not grpmax-eligible) | 0.0416% | 2,404 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0304% | 3,290 |
| East Asian | 0.0178% | 5,608 |
| South Asian | 0.0154% | 6,505 |
| Admixed American | 0.015% | 6,669 |
| European (non-Finnish) | 0.0111% | 9,008 |

*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 **52** lies in the ig-like 1 domain.

**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.Pro52= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (7 Likely benign, 2 Benign, 2 Uncertain significance).

**Submission history:** 11 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-02-07 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-07-02 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-10 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-06 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-09-27 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-10 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-07 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [dilated cardiomyopathy 1G](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1g/), [autosomal recessive limb-girdle muscular dystrophy type 2J](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2j/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, not provided, Cardiomyopathy, Autosomal recessive limb-girdle muscular dystrophy type 2J, Dilated cardiomyopathy 1G, Limb-girdle muscular dystrophy, type 2J, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related TTN variant pages (same residue, condition, or type): [TTN c.100171+1G>A](/variant/ttn-c-100171-plus-1g-a), [TTN c.100766-1G>T](/variant/ttn-c-100766-minus-1g-t), [TTN c.100766-2A>T](/variant/ttn-c-100766-minus-2a-t), [TTN c.106375-2A>G](/variant/ttn-c-106375-minus-2a-g), [TTN c.106531+1G>A](/variant/ttn-c-106531-plus-1g-a), [TTN c.107224-1G>C](/variant/ttn-c-107224-minus-1g-c), [TTN c.107377+1G>A](/variant/ttn-c-107377-plus-1g-a), [TTN c.107377+1G>C](/variant/ttn-c-107377-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 166360). 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.*