Is VDR p.Arg18Trp (c.52C>T) pathogenic?

VDR p.Arg18Trp (c.52C>T) is classified Conflicting classifications of pathogenicity in VDR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.5725); Ultra-rare (popmax 0.0413%, afr); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Arg18Trp (c.52C>T)?

VDR p.Arg18Trp (c.52C>T) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Arg18Trp (c.52C>T) in the general population?

VDR p.Arg18Trp (c.52C>T) is ultra-rare (popmax 0.0413%, 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.Arg18Trp (c.52C>T)?

AlphaMissense predicts likely pathogenic (score 0.5725) — an in-silico prediction, not a clinical call.

VDR p.Arg18Trp

c.52C>T · rs147496897 · VCV882356

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

vitamin D-dependent rickets, type 2A

Computational evidence

Protein change
AlphaMissense	0.5725	likely pathogenic
REVEL	0.631	indeterminate
SaProt	LLR -8.78	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 5.2	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.98 · regional, not allelic
Overall
CADD	28.3	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 0.0413% African / African-American · 31/75,040 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0238% 384/1,614,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.324%	308
Remaining individualsnot grpmax-eligible	0.048%	2,084
African / African-Americangrpmax	0.0413%	2,421
Middle Eastern	0.033%	3,031
South Asian	0.0307%	3,253
Finnishnot grpmax-eligible	0.025%	4,002
East Asian	0.0178%	5,610
European (non-Finnish)	0.0145%	6,901
Admixed American	0.00333%	30,010

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.Arg18Trp
Coding: c.52C>T
MANE Select: NM_000376
dbSNP: rs147496897
Type: single nucleotide variant
Location: chr12:47879062 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB

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.Arg18= Likely benign ★ same residue
VDR p.Arg18Gln Uncertain significance ⚠ 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.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-arg18trp (accessed [today's date]).

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