Is VDR p.Arg274Cys (c.820C>T) pathogenic?

VDR p.Arg274Cys (c.820C>T) is classified Uncertain significance in VDR (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-25). AlphaMissense: likely pathogenic (0.895); Very rare (popmax 0.00267%, afr); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Arg274Cys (c.820C>T)?

VDR p.Arg274Cys (c.820C>T) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Arg274Cys (c.820C>T) in the general population?

VDR p.Arg274Cys (c.820C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Hypocalcemic vitamin D-resistant rickets inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about VDR p.Arg274Cys (c.820C>T)?

AlphaMissense predicts likely pathogenic (score 0.895) — an in-silico prediction, not a clinical call.

VDR p.Arg274Cys

c.820C>T · rs757881350 · VCV3064965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

vitamin D-dependent rickets, type 2A

Computational evidence

Protein change
AlphaMissense	0.895	likely pathogenic
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -11.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,040 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,876 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,520
Admixed American	0.00167%	60,022

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VDR
Protein: p.Arg274Cys
Coding: c.820C>T
MANE Select: NM_000376
dbSNP: rs757881350
Type: single nucleotide variant
Location: chr12:47846744 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 274: 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

Full VDR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

vitamin D-dependent rickets, type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypocalcemic vitamin D-resistant rickets (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VDR p.Arg274His Pathogenic/Likely pathogenic ★★ ⚠ same residue
VDR p.Arg274Leu Pathogenic same residue
VDR p.Arg274Pro Uncertain significance ★ ⚠ same residue
VDR p.Arg30Ter Pathogenic ★★ same condition
VDR p.Arg343Cys Likely pathogenic ★★ same condition
VDR p.Arg391His Pathogenic ★★ same condition
VDR p.Arg50Ter Pathogenic ★★ same condition
VDR p.Arg73Gln Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vdr-p-arg274cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown