Is VDR p.Ser256Ala (c.766T>G) pathogenic?

VDR p.Ser256Ala (c.766T>G) is classified Uncertain significance in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0528); Very rare (popmax 0.00186%, nfe).

How common is VDR p.Ser256Ala (c.766T>G) in the general population?

VDR p.Ser256Ala (c.766T>G) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about VDR p.Ser256Ala (c.766T>G)?

AlphaMissense predicts likely benign (score 0.0528) — an in-silico prediction, not a clinical call.

VDR p.Ser256Ala

c.766T>G · VCV4280886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0528	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -1.7, phastCons 0.17
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	6.771	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 0.00186% European (non-Finnish) · 22/1,180,040 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00136% 22/1,614,046 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.Ser256Ala
Coding: c.766T>G
MANE Select: NM_000376
Type: single nucleotide variant
Location: chr12:47846798 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 256: 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; the 'interaction with coactivator lxxll motif' region

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-ser256ala (accessed [today's date]).

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