Is VDR p.Pro372Leu (c.1115C>T) pathogenic?

VDR p.Pro372Leu (c.1115C>T) is classified Uncertain significance in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: likely benign (0.1302); Very rare (popmax 0.00667%, amr).

How common is VDR p.Pro372Leu (c.1115C>T) in the general population?

VDR p.Pro372Leu (c.1115C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about VDR p.Pro372Leu (c.1115C>T)?

AlphaMissense predicts likely benign (score 0.1302) — an in-silico prediction, not a clinical call.

VDR p.Pro372Leu

c.1115C>T · rs771926584 · VCV1040776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1302	likely benign
REVEL	0.723	pathogenic-leaning
SaProt	LLR -8.48	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	26.6	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 0.00667% Admixed American · 4/59,998 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00136% 22/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
South Asian	0.00549%	18,219
East Asian	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,488
Finnishnot grpmax-eligible	0.00156%	64,020
European (non-Finnish)	0.000847%	118,002

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.Pro372Leu
Coding: c.1115C>T
MANE Select: NM_000376
dbSNP: rs771926584
Type: single nucleotide variant
Location: chr12:47844915 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 372: 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

Similar variants

VDR p.Pro372= Likely benign ★★ same residue
VDR p.Arg274His Pathogenic/Likely pathogenic ★★ ⚠ same type
VDR p.Arg30Ter Pathogenic ★★ same type
VDR p.Arg343Cys Likely pathogenic ★★ same type
VDR p.Arg391His Pathogenic ★★ same type
VDR p.Arg50Ter Pathogenic ★★ same type
VDR p.Arg73Gln Pathogenic/Likely pathogenic ★★ same type
VDR p.Arg73Ter Pathogenic ★★ same type

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-pro372leu (accessed [today's date]).

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