Is VDR p.Phe406Ile (c.1216T>A) pathogenic?

VDR p.Phe406Ile (c.1216T>A) is classified Uncertain significance in VDR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-10). AlphaMissense: likely benign (0.2699); Very rare (popmax 0.00797%, nfe); Associated with Inborn genetic diseases.

What condition is associated with VDR p.Phe406Ile (c.1216T>A)?

VDR p.Phe406Ile (c.1216T>A) is associated with Inborn genetic diseases (ClinVar).

How common is VDR p.Phe406Ile (c.1216T>A) in the general population?

VDR p.Phe406Ile (c.1216T>A) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about VDR p.Phe406Ile (c.1216T>A)?

AlphaMissense predicts likely benign (score 0.2699) — an in-silico prediction, not a clinical call.

VDR p.Phe406Ile

c.1216T>A · rs1245498873 · VCV1917095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2699	likely benign
REVEL	0.548	indeterminate
SaProt	LLR -3.79	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 2.9	GERP -0.66, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	15.2	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 0.00797% European (non-Finnish) · 94/1,180,016 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00613% 99/1,614,052 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,553
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00133%	74,930

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.Phe406Ile
Coding: c.1216T>A
MANE Select: NM_000376
dbSNP: rs1245498873
Type: single nucleotide variant
Location: chr12:47844814 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 406: 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)

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.Phe406Tyr Uncertain significance ★ ⚠ 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-phe406ile (accessed [today's date]).

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