Is VDR p.Arg368His (c.1103G>A) pathogenic?

VDR p.Arg368His (c.1103G>A) is classified Uncertain significance in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-23). AlphaMissense: likely benign (0.0814); Very rare (popmax 0.00223%, eas).

How common is VDR p.Arg368His (c.1103G>A) in the general population?

VDR p.Arg368His (c.1103G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about VDR p.Arg368His (c.1103G>A)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

VDR p.Arg368His

c.1103G>A · rs376903517 · VCV2075756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	23.1	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 0.00223% East Asian · 1/44,866 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,866
Remaining individualsnot grpmax-eligible	0.0016%	62,506
African / African-American	0.00133%	75,030
European (non-Finnish)	0.000169%	589,995

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.Arg368His
Coding: c.1103G>A
MANE Select: NM_000376
dbSNP: rs376903517
Type: single nucleotide variant
Location: chr12:47844927 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 368: 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.Arg368Cys Uncertain significance ★★ ⚠ same residue
VDR p.Arg368Leu 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

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-arg368his (accessed [today's date]).

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