Is VDR p.Tyr366His (c.1096T>C) pathogenic?

VDR p.Tyr366His (c.1096T>C) is classified Uncertain significance in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.887); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with VDR p.Tyr366His (c.1096T>C)?

VDR p.Tyr366His (c.1096T>C) is associated with Inborn genetic diseases (ClinVar).

How common is VDR p.Tyr366His (c.1096T>C) in the general population?

VDR p.Tyr366His (c.1096T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VDR p.Tyr366His (c.1096T>C)?

AlphaMissense predicts likely pathogenic (score 0.887) — an in-silico prediction, not a clinical call.

VDR p.Tyr366His

c.1096T>C · VCV4634358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.887 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.887	likely pathogenic
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -10.80	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VDR
Protein: p.Tyr366His
Coding: c.1096T>C
MANE Select: NM_000376
Type: single nucleotide variant
Location: chr12:47844934 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 366: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VDR p.Tyr366= Conflicting classifications of pathogenicity ★ same residue
VDR c.147-5G>A Uncertain significance ★★ same condition
VDR p.Arg130His Uncertain significance ★★ ⚠ same condition
VDR p.Arg368Leu Uncertain significance ★★ ⚠ same condition
VDR p.Asp181Asn Uncertain significance ★★ ⚠ same condition
VDR p.Asp181Gly Uncertain significance ★★ ⚠ same condition
VDR p.Asp253Glu Uncertain significance ★★ ⚠ same condition
VDR p.Asp292His Uncertain significance ★★ ⚠ 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-tyr366his (accessed [today's date]).

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