Is VDR p.Arg67His (c.200G>A) pathogenic?

VDR p.Arg67His (c.200G>A) is classified Uncertain significance in VDR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0894); Very rare (popmax 0.0028%, nfe).

How common is VDR p.Arg67His (c.200G>A) in the general population?

VDR p.Arg67His (c.200G>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about VDR p.Arg67His (c.200G>A)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

VDR p.Arg67His

c.200G>A · rs753383761 · VCV1009301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -5.70	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 2.7	GERP -1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.98 · regional, not allelic
Overall
CADD	22.1	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 0.0028% European (non-Finnish) · 33/1,179,764 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00223% 36/1,613,710 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,233
European (non-Finnish)grpmax	0.0028%	35,750
Finnishnot grpmax-eligible	0.00156%	63,968

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.Arg67His
Coding: c.200G>A
MANE Select: NM_000376
dbSNP: rs753383761
Type: single nucleotide variant
Location: chr12:47865124 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 52 PDB
Residue 67: a DNA-binding region

Full VDR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VDR p.Arg67Cys Uncertain significance ★★ ⚠ same residue
VDR p.Arg67= 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

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-arg67his (accessed [today's date]).

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