Is VDR p.Pro155Thr (c.463C>A) pathogenic?

VDR p.Pro155Thr (c.463C>A) is classified Uncertain significance in VDR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-01-06). AlphaMissense: ambiguous (0.4252); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with VDR p.Pro155Thr (c.463C>A)?

VDR p.Pro155Thr (c.463C>A) is associated with Inborn genetic diseases (ClinVar).

How common is VDR p.Pro155Thr (c.463C>A) in the general population?

VDR p.Pro155Thr (c.463C>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about VDR p.Pro155Thr (c.463C>A)?

AlphaMissense predicts ambiguous (score 0.4252) — an in-silico prediction, not a clinical call.

VDR p.Pro155Thr

c.463C>A · rs201814357 · VCV1006650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4252 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4252	ambiguous
REVEL	0.652	pathogenic-leaning
SaProt	LLR -7.99	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.52, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 431 bp · p 7e-05 · regional, not allelic
Overall
CADD	23.7	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 0.0107% African / African-American · 8/75,066 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000496% 8/1,614,186 alleles · ultra-rare exomes 2/1,461,844 · genomes 6/152,342 · joint denominator

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.Pro155Thr
Coding: c.463C>A
MANE Select: NM_000376
dbSNP: rs201814357
Type: single nucleotide variant
Location: chr12:47857249 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 155: 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 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
VDR p.Phe406Ile 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-pro155thr (accessed [today's date]).

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