# NM_000376.3(VDR):c.909C>T (p.Ala303=)

https://sugi.bio/variant/vdr-p-ala303

## Summary

**VDR p.Ala303= (c.909C>T)** is classified **Conflicting classifications of pathogenicity** in VDR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-24). Rare (popmax 0.381%, nfe); Associated with vitamin D-dependent rickets, type 2A.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs12721365 · 7 submitters · 1 linked condition · rare (popmax 0.381%, nfe)

## For patients & families {#patients}

This is a change in the VDR gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to vitamin D-dependent rickets, type 2A.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | VDR is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Hypocalcemic vitamin D-resistant rickets** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperparathyroidism — Very frequent (99-80%)
- Joint dislocation — Very frequent (99-80%)
- Hypophosphatemia — Very frequent (99-80%)
- Bone pain — Very frequent (99-80%)
- Osteomalacia — Very frequent (99-80%)
- Recurrent fractures — Very frequent (99-80%)
- Osteolysis — Very frequent (99-80%)
- Hypocalcemia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018169/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VDR](https://sugi.bio/atlas/gene/VDR/) |
| Protein change (HGVS p.) | p.Ala303= |
| Coding change (HGVS c.) | c.909C>T |
| MANE Select transcript | [NM_000376](https://www.ncbi.nlm.nih.gov/nuccore/NM_000376) |
| dbSNP | [rs12721365](https://www.ncbi.nlm.nih.gov/snp/rs12721365/) |
| Variant type | single nucleotide variant |
| Location | chr12:47846450-47846450 (GRCh38) |
| ClinVar | [VCV308880](https://www.ncbi.nlm.nih.gov/clinvar/variation/308880/) |

**All HGVS expressions:** `NC_000012.11:g.48240233G>A`, `NC_000012.12:g.47846450G>A`, `NG_008731.1:g.63582C>T`, `NM_000376.3:c.909C>T`, `NM_001017535.2:c.909C>T`, `NM_001017536.2:c.1059C>T`, `NM_001364085.2:c.909C>T`, `NM_001374661.1:c.909C>T`, `NM_001374662.1:c.909C>T`

## 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 -4.468, GERP -3.46 — fast-evolving / accelerated position
- CADD: **PHRED 0.065**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.99 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.381%** (nfe) · FAF95 0.372% · FAF99 0.368% · 4,396/1,153,792 in the highest group · 4,972/1,563,288 alleles overall — rare (popmax 0.381%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.381% | 262 |
| Remaining individuals (not grpmax-eligible) | 0.29% | 345 |
| Finnish (not grpmax-eligible) | 0.185% | 541 |
| South Asian | 0.175% | 572 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.174% | 575 |
| Amish (not grpmax-eligible) | 0.11% | 912 |
| Admixed American | 0.0767% | 1,304 |
| African / African-American | 0.0624% | 1,603 |
| Middle Eastern | 0.0334% | 2,992 |
| East Asian | 0.00238% | 41,992 |

*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}

**VDR** population constraint: LOEUF 0.714, pLI 0.01086, missense-Z 2.1968. *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 **303** lies in the nr lbd domain; a UniProt-annotated variant site (in vddr2a; loss of calcitriol receptor activity; loss of affinity for calcitriol; no effect on ligand-independent localization to the nucleus); a turn.

AlphaFold model confidence (whole protein): pLDDT 84.56, 74% of residues very-high.

**52 experimental structure(s)** (PDB): [1DB1](https://www.rcsb.org/structure/1DB1), [1IE8](https://www.rcsb.org/structure/1IE8), [1IE9](https://www.rcsb.org/structure/1IE9), [1KB2](https://www.rcsb.org/structure/1KB2), [1KB4](https://www.rcsb.org/structure/1KB4), [1KB6](https://www.rcsb.org/structure/1KB6) — incl. mutant structure 3M7R.

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

*Describes the biological roles of VDR (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:** VDR's established molecular role includes DNA binding. p.Ala303= falls in the nr lbd domain.


### Pathways affected {#pathways}

VDR participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | curated |
| [Vitamin D (calciferol) metabolism](https://reactome.org/content/detail/R-HSA-196791) | curated |

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

**Molecular function:** DNA binding, nuclear receptor activity, bile acid nuclear receptor activity, nuclear retinoid X receptor binding, calcitriol binding, lithocholic acid binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, cell morphogenesis, negative regulation of cell population proliferation, positive regulation of gene expression, negative regulation of keratinocyte proliferation, phosphate ion transmembrane transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-24.

**Submitter consensus:** conflicting (4 Likely benign, 2 Benign, 1 Uncertain significance).

**Submission history:** 7 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2016-11-07 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2025-07-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-24 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[vitamin D-dependent rickets, type 2A](https://sugi.bio/atlas/disease/vitamin-d-dependent-rickets-type-2a/).

**Reported phenotype names (ClinVar):** Vitamin D-dependent rickets type II with alopecia, not specified, not provided, AllHighlyPenetrant, none provided, Vitamin D-dependent rickets, type 2A, PDDR IIA, PSEUDOVITAMIN D-DEFICIENCY, TYPE IIA, RICKETS, HEREDITARY VITAMIN D-RESISTANT, RICKETS-ALOPECIA SYNDROME.

## Similar variants {#similar}

Related VDR variant pages (same residue, condition, or type): [VDR p.Arg274His](/variant/vdr-p-arg274his), [VDR p.Arg30Ter](/variant/vdr-p-arg30ter), [VDR p.Arg343Cys](/variant/vdr-p-arg343cys), [VDR p.Arg391His](/variant/vdr-p-arg391his), [VDR p.Arg50Ter](/variant/vdr-p-arg50ter), [VDR p.Arg73Gln](/variant/vdr-p-arg73gln), [VDR p.Arg73Ter](/variant/vdr-p-arg73ter), [VDR p.Tyr295Ter](/variant/vdr-p-tyr295ter).

### 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 308880). 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.*