Is VDR p.Asp299= (c.897C>T) pathogenic?

VDR p.Asp299= (c.897C>T) is classified Likely benign in VDR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-08). Very rare (popmax 0.00401%, afr); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Asp299= (c.897C>T)?

VDR p.Asp299= (c.897C>T) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Asp299= (c.897C>T) in the general population?

VDR p.Asp299= (c.897C>T) is very rare (popmax 0.00401%, afr) (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.Asp299=

c.897C>T · rs746128447 · VCV1555177

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -3
Overall
CADD	1.626	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,902 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.0018% 29/1,613,622 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,961
Remaining individualsnot grpmax-eligible	0.00801%	12,489
African / African-Americangrpmax	0.00401%	24,967
European (non-Finnish)	0.000932%	107,276

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.

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.Asp299=
Coding: c.897C>T
MANE Select: NM_000376
dbSNP: rs746128447
Type: single nucleotide variant
Location: chr12:47846667 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 299: 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); 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 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-asp299 (accessed [today's date]).

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