# NM_003673.4(TCAP):c.504AG[1] (p.Ter168=)

https://sugi.bio/variant/tcap-p-ter168

## Summary

**TCAP p.Ter168= (c.504AG[1])** is classified **Uncertain significance** in TCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-06). Very rare (popmax 8.48e-05%, nfe); Associated with hypertrophic cardiomyopathy 25.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2057253961 · 1 submitter · 2 linked conditions · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the TCAP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hypertrophic cardiomyopathy 25.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024827/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TCAP](https://sugi.bio/atlas/gene/TCAP/) |
| Protein change (HGVS p.) | p.Ter168= |
| Coding change (HGVS c.) | c.504AG[1] |
| MANE Select transcript | [NM_003673](https://www.ncbi.nlm.nih.gov/nuccore/NM_003673) |
| dbSNP | [rs2057253961](https://www.ncbi.nlm.nih.gov/snp/rs2057253961/) |
| Variant type | Microsatellite |
| Location | chr17:39666108-39666109 (GRCh38) |
| ClinVar | [VCV1046017](https://www.ncbi.nlm.nih.gov/clinvar/variation/1046017/) |

**All HGVS expressions:** `LRG_210:g.5764AG[1]`, `NC_000017.10:g.37822362AG[1]`, `NC_000017.11:g.39666109AG[1]`, `NG_008892.1:g.5764AG[1]`, `NG_042278.1:g.3129AG[1]`, `NM_003673.4:c.504AG[1]`

## 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 7.927, GERP 2.64, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **stop-loss** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.374, pLI 3.7212e-05. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,888 in the highest group · 1/1,599,636 alleles overall — very rare (popmax 8.48e-05%, 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}

**TCAP** population constraint: LOEUF 1.374, pLI 3.7212e-05, missense-Z 0.3455. *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** — Limited (AD)
- **hypertrophic cardiomyopathy** — Disputed (AD)
- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.89, 49% of residues very-high.

**2 experimental structure(s)** (PDB): [1YA5](https://www.rcsb.org/structure/1YA5), [2F8V](https://www.rcsb.org/structure/2F8V).

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

*Describes the biological roles of TCAP (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:** TCAP's established molecular role includes structural constituent of muscle.


### Pathways affected {#pathways}

TCAP 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:** structural constituent of muscle, protein-macromolecule adaptor activity, titin binding, BMP binding, transmembrane transporter binding, FATZ binding.

**Biological process:** skeletal muscle contraction, cardiac muscle hypertrophy, adult heart development, cardiac muscle hypertrophy in response to stress, skeletal muscle thin filament assembly, skeletal muscle myosin thick filament assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-06 |

## Associated conditions {#conditions}

[hypertrophic cardiomyopathy 25](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-25/), [familial hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/familial-hypertrophic-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Hypertrophic cardiomyopathy 25, Primary familial hypertrophic cardiomyopathy, CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 25.

## Similar variants {#similar}

Related TCAP variant pages (same residue, condition, or type): [TCAP p.Glu105del](/variant/tcap-p-glu105del), [TCAP p.Glu43del](/variant/tcap-p-glu43del), [TCAP p.Arg18fs](/variant/tcap-p-arg18fs), [TCAP p.Cys15_Glu16delinsTer](/variant/tcap-p-cys15-glu16delinster), [TCAP p.Glu13del](/variant/tcap-p-glu13del), [TCAP p.Met69del](/variant/tcap-p-met69del), [TCAP p.Glu120fs](/variant/tcap-p-glu120fs), [TCAP p.Ter168Trp](/variant/tcap-p-ter168trp).

### 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 1046017). 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.*