# NM_032588.4(TRIM63):c.481_482del (p.Ser161fs)

https://sugi.bio/variant/trim63-p-ser161fs

## Summary

**TRIM63 p.Ser161fs (c.481_482del)** is classified **Pathogenic** in TRIM63 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-24). Ultra-rare (popmax 0.0177%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs540072010 · 5 submitters · 3 linked conditions · ultra-rare (popmax 0.0177%, nfe)

## For patients & families {#patients}

This is a change in the TRIM63 gene that is considered disease-causing, submitted by 5 submitters, and is linked to Inborn genetic diseases.

*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 | [TRIM63](https://sugi.bio/atlas/gene/TRIM63/) |
| Protein change (HGVS p.) | p.Ser161fs |
| Coding change (HGVS c.) | c.481_482del |
| MANE Select transcript | [NM_032588](https://www.ncbi.nlm.nih.gov/nuccore/NM_032588) |
| dbSNP | [rs540072010](https://www.ncbi.nlm.nih.gov/snp/rs540072010/) |
| Variant type | Microsatellite |
| Location | chr1:26061185-26061186 (GRCh38) |
| ClinVar | [VCV985254](https://www.ncbi.nlm.nih.gov/clinvar/variation/985254/) |

**All HGVS expressions:** `LRG_757:g.11447AG[1]`, `LRG_757t1:c.481_482del`, `NC_000001.10:g.26387676CT[1]`, `NC_000001.11:g.26061185CT[1]`, `NG_033268.1:g.11447AG[1]`, `NM_032588.4:c.481_482del`, `NM_032588.4:c.481_482delAG`

## 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 -0.6, GERP -4.54 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.329, pLI 1.3752e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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** — 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 **0.0177%** (nfe) · FAF95 0.0157% · FAF99 0.015% · 209/1,179,960 in the highest group · 225/1,613,958 alleles overall — ultra-rare (popmax 0.0177%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0177% | 5,646 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0169% | 5,919 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,944 |
| African / African-American | 0.00267% | 37,509 |

*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}

**TRIM63** population constraint: LOEUF 1.329, pLI 1.3752e-15, missense-Z -0.08117. *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):

- **hypertrophic cardiomyopathy** — Moderate (AR)
- **hypertrophic cardiomyopathy** — Disputed (AD)

## Protein context {#protein}

Residue **161** lies in the 'interaction with ttn' region; a turn.

AlphaFold model confidence (whole protein): pLDDT 82.88, 57% of residues very-high.

**3 experimental structure(s)** (PDB): [2D8U](https://www.rcsb.org/structure/2D8U), [3DDT](https://www.rcsb.org/structure/3DDT), [4M3L](https://www.rcsb.org/structure/4M3L).

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

*Describes the biological roles of TRIM63 (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:** TRIM63's established molecular role includes titin binding. p.Ser161fs falls in the interaction with ttn region.


### Pathways affected {#pathways}

TRIM63 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes](https://reactome.org/content/detail/R-HSA-9615017) | electronic |

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

**Molecular function:** titin binding, ubiquitin protein ligase activity.

**Biological process:** negative regulation of glycolytic process.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-24.

**Submitter consensus:** unanimous (5/5 Pathogenic).

**Submission history:** 5 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-14 |
| Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-07 |
| Centre of Medical Genetics, University Hospital Muenster | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-08 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2025-07-18 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-24 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy/), [cardiomyopathy, familial hypertrophic, 31](https://sugi.bio/atlas/disease/cardiomyopathy-familial-hypertrophic-31/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Hypertrophic cardiomyopathy, See cases, Cardiomyopathy, familial hypertrophic, 31, HYPERTROPHIC MYOCARDIOPATHY.

## Similar variants {#similar}

Related TRIM63 variant pages (same residue, condition, or type): [TRIM63 p.Arg112Gln](/variant/trim63-p-arg112gln), [TRIM63 p.Arg183His](/variant/trim63-p-arg183his), [TRIM63 p.Arg230Trp](/variant/trim63-p-arg230trp), [TRIM63 p.Arg62Gln](/variant/trim63-p-arg62gln), [TRIM63 p.Arg79Cys](/variant/trim63-p-arg79cys), [TRIM63 p.Gln190Lys](/variant/trim63-p-gln190lys), [TRIM63 p.Pro113Leu](/variant/trim63-p-pro113leu), [TRIM63 p.Pro57Arg](/variant/trim63-p-pro57arg).

### 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 985254). 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.*