Is VDR p.Ala303= (c.909C>T) pathogenic?

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.

What condition is associated with VDR p.Ala303= (c.909C>T)?

VDR p.Ala303= (c.909C>T) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Ala303= (c.909C>T) in the general population?

VDR p.Ala303= (c.909C>T) is rare (popmax 0.381%, nfe) (gnomAD).

How is Hypocalcemic vitamin D-resistant rickets inherited?

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

VDR p.Ala303=

c.909C>T · rs12721365 · VCV308880

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.381%, nfe)

Conditions

vitamin D-dependent rickets, type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.5	GERP -3.5
Overall
CADD	0.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.381% European (non-Finnish) · 4,396/1,153,792 alleles

Filtering AF 0.372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.368%

Overall 0.318% 4,972/1,563,288 alleles · rare exomes 4,677/1,411,000 · genomes 295/152,288 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.381%	262
Remaining individualsnot grpmax-eligible	0.29%	345
Finnishnot grpmax-eligible	0.185%	541
South Asian	0.175%	572
Ashkenazi Jewishnot grpmax-eligible	0.174%	575
Amishnot 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

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.Ala303=
Coding: c.909C>T
MANE Select: NM_000376
dbSNP: rs12721365
Type: single nucleotide variant
Location: chr12:47846450 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 303: 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

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 condition
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
VDR p.Arg73Ter Pathogenic ★★ same condition
VDR p.Tyr295Ter 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-ala303 (accessed [today's date]).

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