Is VDR p.Pro312Ser (c.934C>T) pathogenic?

VDR p.Pro312Ser (c.934C>T) is classified Uncertain significance in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-02). AlphaMissense: likely pathogenic (0.8646); Very rare (popmax 0.00188%, amr).

How common is VDR p.Pro312Ser (c.934C>T) in the general population?

VDR p.Pro312Ser (c.934C>T) is very rare (popmax 0.00188%, amr) (gnomAD).

What do computational predictors say about VDR p.Pro312Ser (c.934C>T)?

AlphaMissense predicts likely pathogenic (score 0.8646) — an in-silico prediction, not a clinical call.

VDR p.Pro312Ser

c.934C>T · VCV3907456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00188%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8646	likely pathogenic
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	31.0	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 0.00188% Admixed American · 1/53,148 alleles

Overall 7.06e-05% 1/1,416,832 alleles · very rare

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.Pro312Ser
Coding: c.934C>T
MANE Select: NM_000376
Type: single nucleotide variant
Location: chr12:47846425 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 312: 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

Similar variants

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
VDR p.Tyr295Ter 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-pro312ser (accessed [today's date]).

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