# NM_001267550.2(TTN):c.103236C>T (p.Ile34412=)

https://sugi.bio/variant/ttn-p-ile34412

## Summary

**TTN p.Ile34412= (c.103236C>T)** is classified **Likely benign** in TTN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-29). Very rare (popmax 0.00935%, afr); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs745465328 · 4 submitters · 3 linked conditions · very rare (popmax 0.00935%, afr)

## For patients & families {#patients}

This is a change in the TTN gene that is classified as likely benign — not considered disease-causing, submitted by 4 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.Ile34412= |
| Coding change (HGVS c.) | c.103236C>T |
| MANE Select transcript | [NM_001267550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001267550) |
| dbSNP | [rs745465328](https://www.ncbi.nlm.nih.gov/snp/rs745465328/) |
| Variant type | single nucleotide variant |
| Location | chr2:178533379-178533379 (GRCh38) |
| ClinVar | [VCV385973](https://www.ncbi.nlm.nih.gov/clinvar/variation/385973/) |

**All HGVS expressions:** `LRG_391:g.302424C>T`, `NC_000002.11:g.179398106G>A`, `NC_000002.12:g.178533379G>A`, `NG_011618.3:g.302424C>T`, `NG_051363.1:g.15553G>A`, `NM_001256850.1:c.98313C>T`, `NM_001267550.2:c.103236C>T`, `NM_003319.4:c.76041C>T`, `NM_133378.4:c.95532C>T`, `NM_133432.3:c.76416C>T`, `NM_133437.4:c.76617C>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 5.275, GERP -0.168, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 0.154**. 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 **0.00935%** (afr) · FAF95 0.00437% · FAF99 0.00309% · 7/74,898 in the highest group · 9/1,613,444 alleles overall — very rare (popmax 0.00935%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00935% | 10,700 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,230 |

*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, triplosensitivity 0 (0–3 scale). *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}


**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.


### 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-29.

**Submitter consensus:** unanimous (4/4 Likely benign).

**Submission history:** 4 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-05-24 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-05 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-29 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [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, Autosomal recessive limb-girdle muscular dystrophy type 2J, Dilated cardiomyopathy 1G, AllHighlyPenetrant, Limb-girdle muscular dystrophy, type 2J, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10.

## 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 2026-10-06); 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 385973). 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.*