# NM_017636.4(TRPM4):c.163del (p.Ala55fs)

https://sugi.bio/variant/trpm4-p-ala55fs

## Summary

**TRPM4 p.Ala55fs (c.163del)** is classified **Uncertain significance** in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-25). No allele count reported in gnomAD v4.1 (AN 1,603,100); Associated with TRPM4-related disorder.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,603,100)

## For patients & families {#patients}

This is a change in the TRPM4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to TRPM4-related disorder.

*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 | [TRPM4](https://sugi.bio/atlas/gene/TRPM4/) |
| Protein change (HGVS p.) | p.Ala55fs |
| Coding change (HGVS c.) | c.163del |
| MANE Select transcript | [NM_017636](https://www.ncbi.nlm.nih.gov/nuccore/NM_017636) |
| Variant type | Deletion |
| Location | chr19:49166108-49166108 (GRCh38) |
| ClinVar | [VCV4852460](https://www.ncbi.nlm.nih.gov/clinvar/variation/4852460/) |

**All HGVS expressions:** `NC_000019.10:g.49166111del`, `NC_000019.9:g.49669368del`, `NG_027551.2:g.13353del`, `NG_141808.1:g.241del`, `NM_001195227.2:c.163del`, `NM_001321281.2:c.163del`, `NM_001321282.2:c.-1210del`, `NM_001321283.2:c.-74-2149del`, `NM_001321285.2:c.-237-2442del`, `NM_017636.4:c.163del`, `NM_017636.4:c.163delG`

## 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 -4.24 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.084, pLI 1.4032e-39. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 25**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,603,100)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**TRPM4** population constraint: LOEUF 1.084, pLI 1.4032e-39, missense-Z -0.097407. *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):

- **Brugada syndrome** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.51, 27% of residues very-high.

**42 experimental structure(s)** (PDB): [30KZ](https://www.rcsb.org/structure/30KZ), [30LD](https://www.rcsb.org/structure/30LD), [5WP6](https://www.rcsb.org/structure/5WP6), [6BQR](https://www.rcsb.org/structure/6BQR), [6BQV](https://www.rcsb.org/structure/6BQV), [6BWI](https://www.rcsb.org/structure/6BWI) — incl. mutant structure 9B94.

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

*Describes the biological roles of TRPM4 (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:** TRPM4's established molecular role includes calcium-activated cation channel activity.


### Pathways affected {#pathways}

TRPM4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TRP channels](https://reactome.org/content/detail/R-HSA-3295583) | curated |
| [Sensory perception of sweet, bitter, and umami (glutamate) taste](https://reactome.org/content/detail/R-HSA-9717207) | electronic |

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

**Molecular function:** calcium-activated cation channel activity, calcium ion binding, identical protein binding.

**Biological process:** regulation of T cell cytokine production, positive regulation of cell population proliferation, protein sumoylation, calcium-mediated signaling, protein homotetramerization, transmembrane transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genomics Laboratory, Stanford Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-25 |

## Associated conditions {#conditions}

[TRPM4-related disorder](https://sugi.bio/atlas/disease/trpm4-related-disorder/).

**Reported phenotype names (ClinVar):** TRPM4-related disorder, TRPM4-related condition, TRPM4-related disorders.

## Similar variants {#similar}

Related TRPM4 variant pages (same residue, condition, or type): [TRPM4 p.Ala55=](/variant/trpm4-p-ala55), [TRPM4 p.Leu829Pro](/variant/trpm4-p-leu829pro), [TRPM4 p.Thr286=](/variant/trpm4-p-thr286), [TRPM4 p.Val586Leu](/variant/trpm4-p-val586leu), [TRPM4 p.Glu7Lys](/variant/trpm4-p-glu7lys), [TRPM4 p.Ile201Val](/variant/trpm4-p-ile201val), [TRPM4 p.Arg250Leu](/variant/trpm4-p-arg250leu), [TRPM4 p.Gly848Ser](/variant/trpm4-p-gly848ser).

### 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 4852460). 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.*