Is VDR p.Arg73Gln (c.218G>A) pathogenic?

VDR p.Arg73Gln (c.218G>A) is classified Pathogenic/Likely pathogenic in VDR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-22). AlphaMissense: likely pathogenic (0.9989); Ultra-rare (popmax 0.025%, amr); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Arg73Gln (c.218G>A)?

VDR p.Arg73Gln (c.218G>A) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Arg73Gln (c.218G>A) in the general population?

VDR p.Arg73Gln (c.218G>A) is ultra-rare (popmax 0.025%, amr) (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.Arg73Gln (c.218G>A)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

VDR p.Arg73Gln

c.218G>A · rs121909791 · VCV7746

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

vitamin D-dependent rickets, type 2A

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 7% in VDR
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -12.54	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.98 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/60,008 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00149% 24/1,613,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,001
Middle Eastern	0.0164%	6,080
African / African-American	0.004%	24,977
South Asian	0.0022%	45,537
European (non-Finnish)	0.000254%	393,281

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.Arg73Gln
Coding: c.218G>A
MANE Select: NM_000376
dbSNP: rs121909791
Type: single nucleotide variant
Location: chr12:47865106 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 73: a DNA-binding region; a UniProt-annotated variant site (in vddr2a); 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.Arg73Ter Pathogenic ★★ same residue
VDR p.Arg73= Likely benign ★★ same residue
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.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-arg73gln (accessed [today's date]).

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