Is VDR p.Ile87Val (c.259A>G) pathogenic?

VDR p.Ile87Val (c.259A>G) is classified Uncertain significance in VDR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-01-03). AlphaMissense: likely benign (0.1908); Very rare (popmax 0.00627%, nfe); Associated with vitamin D-dependent rickets, type 2A.

What condition is associated with VDR p.Ile87Val (c.259A>G)?

VDR p.Ile87Val (c.259A>G) is associated with vitamin D-dependent rickets, type 2A (ClinVar).

How common is VDR p.Ile87Val (c.259A>G) in the general population?

VDR p.Ile87Val (c.259A>G) is very rare (popmax 0.00627%, 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.Ile87Val (c.259A>G)?

AlphaMissense predicts likely benign (score 0.1908) — an in-silico prediction, not a clinical call.

VDR p.Ile87Val

c.259A>G · rs387907555 · VCV64425

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00627%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

vitamin D-dependent rickets, type 2A

Computational evidence

Protein change
AlphaMissense	0.1908	likely benign
REVEL	0.582	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.87, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.98 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00627% European (non-Finnish) · 74/1,179,628 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00471% 76/1,613,632 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00627%	15,941
Remaining individualsnot grpmax-eligible	0.0032%	31,233

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.Ile87Val
Coding: c.259A>G
MANE Select: NM_000376
dbSNP: rs387907555
Type: single nucleotide variant
Location: chr12:47865065 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 87: 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.Ile87= 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.Arg73Gln Pathogenic/Likely pathogenic ★★ same condition
VDR p.Arg73Ter 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-ile87val (accessed [today's date]).

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