Is XDH p.Arg508Trp (c.1522C>T) pathogenic?

XDH p.Arg508Trp (c.1522C>T) is classified Uncertain significance in XDH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-18). AlphaMissense: likely pathogenic (0.7629); Very rare (popmax 0.00667%, amr); Associated with xanthinuria type II.

What condition is associated with XDH p.Arg508Trp (c.1522C>T)?

XDH p.Arg508Trp (c.1522C>T) is associated with xanthinuria type II, xanthinuria type I (ClinVar).

How common is XDH p.Arg508Trp (c.1522C>T) in the general population?

XDH p.Arg508Trp (c.1522C>T) is very rare (popmax 0.00667%, amr) (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.Arg508Trp (c.1522C>T)?

AlphaMissense predicts likely pathogenic (score 0.7629) — an in-silico prediction, not a clinical call.

XDH p.Arg508Trp

c.1522C>T · rs778513905 · VCV1497216

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xanthinuria type II

Computational evidence

Protein change
AlphaMissense	0.7629	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -15.41	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 7.5	GERP -1.7, phastCons 1
Overall
CADD	32.0	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

Grpmax group 0.00667% Admixed American · 4/60,008 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00118% 19/1,614,052 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
African / African-American	0.00133%	74,924
European (non-Finnish)	0.00119%	84,288

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: XDH
Protein: p.Arg508Trp
Coding: c.1522C>T
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs778513905
Type: single nucleotide variant
Location: chr2:31375460 (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

Also linked: xanthinuria type I

For Hereditary xanthinuria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

XDH p.Arg508Gln Uncertain significance ★★ ⚠ same residue
XDH p.Arg508Pro 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-arg508trp (accessed [today's date]).

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