Is VDR p.Ile338= (c.1014C>T) pathogenic?

VDR p.Ile338= (c.1014C>T) is classified Likely benign in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). Very rare (popmax 0.00557%, sas).

How common is VDR p.Ile338= (c.1014C>T) in the general population?

VDR p.Ile338= (c.1014C>T) is very rare (popmax 0.00557%, sas) (gnomAD).

VDR p.Ile338=

c.1014C>T · rs750175824 · VCV1924573

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00557%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -3.8
Overall
CADD	2.019	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00557% South Asian · 5/89,756 alleles

Filtering AF 0.00213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00275% 40/1,454,788 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00642%	15,577
South Asiangrpmax	0.00557%	17,951
European (non-Finnish)	0.00255%	39,259
East Asian	0.00225%	44,540

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile338=
Coding: c.1014C>T
MANE Select: NM_000376
dbSNP: rs750175824
Type: single nucleotide variant
Location: chr12:47846345 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 338: 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.Ile338Met Uncertain significance ★ ⚠ 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-ile338 (accessed [today's date]).

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