# NM_018646.6(TRPV6):c.958C>T (p.Leu320Phe)

https://sugi.bio/variant/trpv6-p-leu320phe

## Summary

**TRPV6 p.Leu320Phe (c.958C>T)** is classified **Uncertain significance** in TRPV6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-18). AlphaMissense: likely pathogenic (0.6865); Absent from gnomAD v4.1; Associated with hyperparathyroidism, transient neonatal.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TRPV6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hyperparathyroidism, transient neonatal.

*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/0016304/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRPV6](https://sugi.bio/atlas/gene/TRPV6/) |
| Protein change (HGVS p.) | p.Leu320Phe |
| Coding change (HGVS c.) | c.958C>T |
| MANE Select transcript | [NM_018646](https://www.ncbi.nlm.nih.gov/nuccore/NM_018646) |
| Variant type | single nucleotide variant |
| Location | chr7:142875829-142875829 (GRCh38) |
| ClinVar | [VCV4080608](https://www.ncbi.nlm.nih.gov/clinvar/variation/4080608/) |

**All HGVS expressions:** `NC_000007.13:g.142573582G>A`, `NC_000007.14:g.142875829G>A`, `NG_050669.1:g.14917C>T`, `NG_050669.2:g.14916C>T`, `NM_018646.6:c.958C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6865)
- REVEL 0.647 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.408 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.312, GERP 0.402, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.9**. 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 0.88** across the covering region of the MANE Select transcript (142,874,607–142,885,636), spanning 11,029 bp. Chi-square p 0.0025. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**TRPV6** population constraint: LOEUF 0.638, pLI 8.4763e-05, missense-Z 2.6896. *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 80.76, 53% of residues very-high.

**25 experimental structure(s)** (PDB): [6BO8](https://www.rcsb.org/structure/6BO8), [6BO9](https://www.rcsb.org/structure/6BO9), [6BOA](https://www.rcsb.org/structure/6BOA), [6D7S](https://www.rcsb.org/structure/6D7S), [6D7T](https://www.rcsb.org/structure/6D7T), [6E2F](https://www.rcsb.org/structure/6E2F).

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

*Describes the biological roles of TRPV6 (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:** TRPV6's established molecular role includes calcium channel activity.


### Pathways affected {#pathways}

TRPV6 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TRP channels](https://reactome.org/content/detail/R-HSA-3295583) | curated |

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

**Molecular function:** calcium channel activity, calmodulin binding.

**Biological process:** calcium ion transport, calcium ion transmembrane transport, calcium ion import across plasma membrane.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-18 |

## Associated conditions {#conditions}

[hyperparathyroidism, transient neonatal](https://sugi.bio/atlas/disease/hyperparathyroidism-transient-neonatal/).

**Reported phenotype names (ClinVar):** Hyperparathyroidism, transient neonatal.

## Similar variants {#similar}

Related TRPV6 variant pages (same residue, condition, or type): [TRPV6 p.Gly451Glu](/variant/trpv6-p-gly451glu), [TRPV6 p.Gly657Arg](/variant/trpv6-p-gly657arg), [TRPV6 p.His205Arg](/variant/trpv6-p-his205arg), [TRPV6 p.Thr238Arg](/variant/trpv6-p-thr238arg), [TRPV6 p.Tyr364=](/variant/trpv6-p-tyr364), [TRPV6 p.Arg425Gln](/variant/trpv6-p-arg425gln), [TRPV6 p.Arg483Trp](/variant/trpv6-p-arg483trp), [TRPV6 p.Cys212Tyr](/variant/trpv6-p-cys212tyr).

### 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 4080608). 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.*