Is VDR p.Arg22Gln (c.65G>A) pathogenic?

VDR p.Arg22Gln (c.65G>A) is classified Uncertain significance in VDR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-28). AlphaMissense: likely pathogenic (0.7804); Ultra-rare (popmax 0.0155%, nfe); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Arg22Gln (c.65G>A)?

VDR p.Arg22Gln (c.65G>A) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Arg22Gln (c.65G>A) in the general population?

VDR p.Arg22Gln (c.65G>A) is ultra-rare (popmax 0.0155%, nfe) (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.Arg22Gln (c.65G>A)?

AlphaMissense predicts likely pathogenic (score 0.7804) — an in-silico prediction, not a clinical call.

VDR p.Arg22Gln

c.65G>A · rs201676749 · VCV880999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

vitamin D-dependent rickets, type 2A

Computational evidence

Protein change
AlphaMissense	0.7804	likely pathogenic
REVEL	0.606	indeterminate
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.98 · regional, not allelic
Overall
CADD	27.3	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 0.0155% European (non-Finnish) · 183/1,180,010 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0123% 198/1,614,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0155%	6,448
Remaining individualsnot grpmax-eligible	0.0128%	7,811
South Asian	0.00659%	15,181
Finnishnot grpmax-eligible	0.00156%	64,030

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.Arg22Gln
Coding: c.65G>A
MANE Select: NM_000376
dbSNP: rs201676749
Type: single nucleotide variant
Location: chr12:47879049 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 22: a DNA-binding region

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.Arg22Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
VDR p.Arg22Pro Uncertain significance ★ ⚠ same residue
VDR p.Arg22= 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

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-arg22gln (accessed [today's date]).

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