# NM_004621.6(TRPC6):c.131_146del (p.Pro44fs)

https://sugi.bio/variant/trpc6-p-pro44fs

## Summary

**TRPC6 p.Pro44fs (c.131_146del)** is classified **Conflicting classifications of pathogenicity** in TRPC6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-23). Very rare (popmax 0.000256%, nfe); Associated with focal segmental glomerulosclerosis 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · very rare (popmax 0.000256%, nfe)

## For patients & families {#patients}

This is a change in the TRPC6 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to focal segmental glomerulosclerosis 2.

*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/0015362/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRPC6](https://sugi.bio/atlas/gene/TRPC6/) |
| Protein change (HGVS p.) | p.Pro44fs |
| Coding change (HGVS c.) | c.131_146del |
| MANE Select transcript | [NM_004621](https://www.ncbi.nlm.nih.gov/nuccore/NM_004621) |
| Variant type | Deletion |
| Location | chr11:101583358-101583373 (GRCh38) |
| ClinVar | [VCV3598837](https://www.ncbi.nlm.nih.gov/clinvar/variation/3598837/) |

**All HGVS expressions:** `NC_000011.10:g.101583364_101583379del`, `NC_000011.9:g.101454095_101454110del`, `NG_011476.2:g.5556_5571del`, `NM_004621.5:c.131_146del`, `NM_004621.6:c.131_146del`

## 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 -1.139, GERP -1.78 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.708, pLI 6.5085e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 13**, 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 deletion 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 **0.000256%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,171,086 in the highest group · 3/1,594,810 alleles overall — very rare (popmax 0.000256%, 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}

**TRPC6** population constraint: LOEUF 0.708, pLI 6.5085e-08, missense-Z 1.9131. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.98, 34% of residues very-high.

**6 experimental structure(s)** (PDB): [5YX9](https://www.rcsb.org/structure/5YX9), [6UZ8](https://www.rcsb.org/structure/6UZ8), [6UZA](https://www.rcsb.org/structure/6UZA), [7A6U](https://www.rcsb.org/structure/7A6U), [7DXF](https://www.rcsb.org/structure/7DXF), [7DXG](https://www.rcsb.org/structure/7DXG).

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

*Describes the biological roles of TRPC6 (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:** TRPC6's established molecular role includes monoatomic cation channel activity.


### Pathways affected {#pathways}

TRPC6 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Effects of PIP2 hydrolysis](https://reactome.org/content/detail/R-HSA-114508) | curated |
| [Elevation of cytosolic Ca2+ levels](https://reactome.org/content/detail/R-HSA-139853) | curated |
| [TRP channels](https://reactome.org/content/detail/R-HSA-3295583) | curated |
| [Role of second messengers in netrin-1 signaling](https://reactome.org/content/detail/R-HSA-418890) | electronic |

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

**Molecular function:** monoatomic cation channel activity, calcium channel activity, protein homodimerization activity, inositol 1,4,5 trisphosphate binding.

**Biological process:** positive regulation of ion transmembrane transporter activity, positive regulation of calcium ion transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-23.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-10 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-23 |

## Associated conditions {#conditions}

[focal segmental glomerulosclerosis 2](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis-2/).

**Reported phenotype names (ClinVar):** Focal segmental glomerulosclerosis 2, not provided, none provided.

## Similar variants {#similar}

Related TRPC6 variant pages (same residue, condition, or type): [TRPC6 p.Asn805fs](/variant/trpc6-p-asn805fs), [TRPC6 p.Asp873fs](/variant/trpc6-p-asp873fs), [TRPC6 p.Gln889fs](/variant/trpc6-p-gln889fs), [TRPC6 p.Gly794fs](/variant/trpc6-p-gly794fs), [TRPC6 p.Leu454fs](/variant/trpc6-p-leu454fs), [TRPC6 p.Leu614fs](/variant/trpc6-p-leu614fs), [TRPC6 p.Lys585fs](/variant/trpc6-p-lys585fs), [TRPC6 p.Trp514fs](/variant/trpc6-p-trp514fs).

### 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 3598837). 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.*