# NM_001267550.2(TTN):c.104412G>A (p.Arg34804=)

https://sugi.bio/variant/ttn-p-arg34804

## Summary

**TTN p.Arg34804= (c.104412G>A)** is classified **Likely benign** in TTN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-11). Very rare (popmax 0.00167%, amr); Associated with dilated cardiomyopathy 1G.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1559009304 · 2 submitters · 2 linked conditions · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the TTN gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to dilated cardiomyopathy 1G.

*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, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |

**Commonly reported features of Familial isolated dilated cardiomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Left ventricular systolic dysfunction — Very frequent (99-80%)
- Edema — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Arrhythmia — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Orthopnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015363/index) · [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.Arg34804= |
| Coding change (HGVS c.) | c.104412G>A |
| dbSNP | [rs1559009304](https://www.ncbi.nlm.nih.gov/snp/rs1559009304/) |
| Variant type | single nucleotide variant |
| Location | chr2:178532203-178532203 (GRCh38) |
| ClinVar | [VCV2180003](https://www.ncbi.nlm.nih.gov/clinvar/variation/2180003/) |

**All HGVS expressions:** `LRG_391:g.303600G>A`, `LRG_391t1:c.104412G>A`, `NC_000002.11:g.179396930C>T`, `NC_000002.12:g.178532203C>T`, `NG_011618.3:g.303600G>A`, `NG_051363.1:g.14377C>T`, `NM_001256850.1:c.99489G>A`, `NM_001267550.2:c.104412G>A`, `NM_003319.4:c.77217G>A`, `NM_133378.4:c.96708G>A`, `NM_133432.3:c.77592G>A`, `NM_133437.4:c.77793G>A`

## 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 -0.286, GERP -5.39, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.007**. 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 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 **0.00167%** (amr) · 1/60,008 in the highest group · 8/1,461,258 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,925 |
| Admixed American (grpmax) | 0.00167% | 60,008 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-11.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-11 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-23 |

## Associated conditions {#conditions}

[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):** Dilated cardiomyopathy 1G, Autosomal recessive limb-girdle muscular dystrophy type 2J, Cardiovascular phenotype, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10, Limb-girdle muscular dystrophy, type 2J.

### 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 2026-07-14); 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 2180003). 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.*