Is XDH p.Arg508Pro (c.1523G>C) pathogenic?

XDH p.Arg508Pro (c.1523G>C) is classified Uncertain significance in XDH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.9871); Absent from gnomAD v4.1; Associated with xanthinuria type II.

What condition is associated with XDH p.Arg508Pro (c.1523G>C)?

XDH p.Arg508Pro (c.1523G>C) is associated with xanthinuria type II (ClinVar).

How common is XDH p.Arg508Pro (c.1523G>C) in the general population?

XDH p.Arg508Pro (c.1523G>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary xanthinuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about XDH p.Arg508Pro (c.1523G>C)?

AlphaMissense predicts likely pathogenic (score 0.9871) — an in-silico prediction, not a clinical call.

XDH p.Arg508Pro

c.1523G>C · rs148603901 · VCV1713647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9871 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xanthinuria type II

Computational evidence

Protein change
AlphaMissense	0.9871	likely pathogenic · top 4% in XDH
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -16.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -1.3, phastCons 1
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: XDH
Protein: p.Arg508Pro
Coding: c.1523G>C
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs148603901
Type: single nucleotide variant
Location: chr2:31375459 (GRCh38)
Structure: AlphaFold pLDDT 98.06 · 3 PDB

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

Disease context

xanthinuria type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary xanthinuria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

XDH p.Arg508Trp Uncertain significance ★★ ⚠ same residue
XDH p.Arg508Gln Uncertain significance ★★ ⚠ same residue
XDH c.1602+1G>A Likely pathogenic ★★ same condition
XDH c.565-1G>A Likely pathogenic ★★ same condition
XDH p.Arg1283Ter Pathogenic ★★ same condition
XDH p.Arg228Ter Pathogenic/Likely pathogenic ★★ same condition
XDH p.Arg825Ter Pathogenic/Likely pathogenic ★★ same condition
XDH p.Gln251Ter Pathogenic/Likely pathogenic ★★ same condition

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/xdh-p-arg508pro (accessed [today's date]).

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