# NM_001130698.2(TRPC3):c.1675G>C (p.Ala559Pro)

https://sugi.bio/variant/trpc3-p-ala559pro

## Summary

**TRPC3 p.Ala559Pro (c.1675G>C)** is classified **Uncertain significance** in TRPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). Very rare (popmax 8.48e-05%, nfe).

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

## For patients & families {#patients}

This is a change in the TRPC3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [TRPC3](https://sugi.bio/atlas/gene/TRPC3/) |
| Protein change (HGVS p.) | p.Ala559Pro |
| Coding change (HGVS c.) | c.1675G>C |
| MANE Select transcript | [NM_001130698](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130698) |
| Variant type | single nucleotide variant |
| Location | chr4:121910271-121910271 (GRCh38) |
| ClinVar | [VCV4191599](https://www.ncbi.nlm.nih.gov/clinvar/variation/4191599/) |

**All HGVS expressions:** `NC_000004.11:g.122831426C>G`, `NC_000004.12:g.121910271C>G`, `NG_030368.1:g.46484G>C`, `NG_030368.2:g.46789G>C`, `NM_001130698.2:c.1675G>C`, `NM_001366479.2:c.1675G>C`, `NM_003305.2:c.1456G>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.612, GERP 2.19, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.56** across the covering region of the MANE Select transcript (121,904,340–121,910,360), spanning 6,020 bp. Chi-square p 7.1e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.25**, donor loss **0.00**, acceptor gain **0.37**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.37**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,804 in the highest group · 1/1,613,834 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}

**TRPC3** population constraint: LOEUF 0.751, pLI 3.4207e-09, missense-Z 3.1086. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **559** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 78.42, 40% of residues very-high.

**19 experimental structure(s)** (PDB): [5ZBG](https://www.rcsb.org/structure/5ZBG), [6CUD](https://www.rcsb.org/structure/6CUD), [6D7L](https://www.rcsb.org/structure/6D7L), [6DJS](https://www.rcsb.org/structure/6DJS), [7DXB](https://www.rcsb.org/structure/7DXB), [7DXC](https://www.rcsb.org/structure/7DXC) — incl. mutant structure 9OLL.

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

*Describes the biological roles of TRPC3 (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:** TRPC3's established molecular role includes calcium channel activity.


### Pathways affected {#pathways}

TRPC3 participates in **5 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 |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | electronic |
| [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:** calcium channel activity, store-operated calcium channel activity, inositol 1,4,5 trisphosphate binding.

**Biological process:** positive regulation of calcium ion transport into cytosol, response to ATP, response to calcium ion, calcium ion transmembrane transport, positive regulation of cardiac muscle hypertrophy in response to stress.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-13 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related TRPC3 variant pages (same residue, condition, or type): [TRPC3 p.Arg381Cys](/variant/trpc3-p-arg381cys), [TRPC3 p.Arg795Gln](/variant/trpc3-p-arg795gln), [TRPC3 p.Asn728Ser](/variant/trpc3-p-asn728ser), [TRPC3 p.Glu901Lys](/variant/trpc3-p-glu901lys), [TRPC3 p.Ile629Val](/variant/trpc3-p-ile629val), [TRPC3 p.Leu905Val](/variant/trpc3-p-leu905val), [TRPC3 p.Lys710Arg](/variant/trpc3-p-lys710arg), [TRPC3 p.Pro444Ser](/variant/trpc3-p-pro444ser).

### 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 4191599). 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.*