# NM_000376.3(VDR):c.821G>A (p.Arg274His)

https://sugi.bio/variant/vdr-p-arg274his

## Summary

**VDR p.Arg274His (c.821G>A)** is classified **Pathogenic/Likely pathogenic** in VDR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-15). AlphaMissense: likely pathogenic (0.8207); Very rare (popmax 0.0011%, sas); Associated with vitamin D-dependent rickets, type 2A.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121909796 · 7 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the VDR gene that is considered likely disease-causing, 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.Arg274His |
| Coding change (HGVS c.) | c.821G>A |
| MANE Select transcript | [NM_000376](https://www.ncbi.nlm.nih.gov/nuccore/NM_000376) |
| dbSNP | [rs121909796](https://www.ncbi.nlm.nih.gov/snp/rs121909796/) |
| Variant type | single nucleotide variant |
| Location | chr12:47846743-47846743 (GRCh38) |
| ClinVar | [VCV915348](https://www.ncbi.nlm.nih.gov/clinvar/variation/915348/) |

**All HGVS expressions:** `NC_000012.11:g.48240526C>T`, `NC_000012.12:g.47846743C>T`, `NG_008731.1:g.63289G>A`, `NM_000376.3:c.821G>A`, `NM_001017535.2:c.821G>A`, `NM_001017536.2:c.971G>A`, `NM_001364085.2:c.821G>A`, `NM_001374661.1:c.821G>A`, `NM_001374662.1:c.821G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8207) — concordant with the pathogenic call
- REVEL 0.924 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.494 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.64, GERP 1.7, phastCons 1 — highly conserved (agrees)
- 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 0.69** across the covering region of the MANE Select transcript (47,844,749–47,855,665), spanning 10,916 bp. Chi-square p 6.4e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,076 in the highest group · 3/1,461,876 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |
| South Asian (grpmax) | 0.0011% | 91,076 |
| European (non-Finnish) | 8.47e-05% | 1,180,027 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **274** lies in the nr lbd domain; a binding site; 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 UniProt-annotated variant site (in vddr2a; loss of calcitriol receptor activity; decreased affinity for calcitriol by a factor of 1000; no effect on interaction with rxra; changed interaction with ncor1; loss of interaction with ncoa1; no effect on sequence-specific dna-binding); an α-helix.

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.Arg274His 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-15.

**Submitter consensus:** conflicting (5 Likely pathogenic, 2 Pathogenic).

**Submission history:** 7 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-05-03 |
| Dr.Nikuei Genetic Center | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-10 |
| Dubai Health Genomic Medicine Center, Dubai Health | Likely pathogenic | criteria provided, single submitter | research | 2024-10-04 |
| Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-07 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Vitamin D-dependent rickets type II with alopecia, not provided, Rickets, none provided, Vitamin D-dependent rickets, type 2A, GENERALIZED RESISTANCE TO 1,25-DIHYDROXYVITAMIN D, HYPOCALCEMIC VITAMIN D-RESISTANT RICKETS, PDDR IIA, PSEUDOVITAMIN D-DEFICIENCY, TYPE IIA, RICKETS, HEREDITARY VITAMIN D-RESISTANT.

## Same-residue context {#hotspot}

Residue **274** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [VDR p.Arg274Leu](/variant/vdr-p-arg274leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related VDR variant pages (same residue, condition, or type): [VDR p.Arg274Cys](/variant/vdr-p-arg274cys), [VDR p.Arg274Leu](/variant/vdr-p-arg274leu), [VDR p.Arg274Pro](/variant/vdr-p-arg274pro), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 915348). 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.*