Is XDH p.Val348Ile (c.1042G>A) pathogenic?

XDH p.Val348Ile (c.1042G>A) is classified Conflicting classifications of pathogenicity in XDH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.0573); Rare (popmax 0.212%, eas); Associated with xanthinuria type I.

What condition is associated with XDH p.Val348Ile (c.1042G>A)?

XDH p.Val348Ile (c.1042G>A) is associated with xanthinuria type I, xanthinuria type II (ClinVar).

How common is XDH p.Val348Ile (c.1042G>A) in the general population?

XDH p.Val348Ile (c.1042G>A) is rare (popmax 0.212%, eas) (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.Val348Ile (c.1042G>A)?

AlphaMissense predicts likely benign (score 0.0573) — an in-silico prediction, not a clinical call.

XDH p.Val348Ile

c.1042G>A · rs192453952 · VCV744561

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0573 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xanthinuria type I

Computational evidence

Protein change
AlphaMissense	0.0573	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.9	GERP -1.9, phastCons 0.008
Overall
CADD	6.646	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.212% East Asian · 95/44,832 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.165%

Overall 0.00849% 137/1,612,864 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.212%	472
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Finnishnot grpmax-eligible	0.00313%	31,980
South Asian	0.0022%	45,361
European (non-Finnish)	0.0022%	45,364
Admixed American	0.00167%	59,882

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.Val348Ile
Coding: c.1042G>A
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs192453952
Type: single nucleotide variant
Location: chr2:31381723 (GRCh38)
Structure: AlphaFold pLDDT 98.06 · 3 PDB
Residue 348: a UniProt-annotated variant site (in hmnr8); a β-strand

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

Disease context

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

Also linked: xanthinuria type II

For Hereditary xanthinuria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

SORD p.Leu348Ile Benign ★★ 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
XDH p.Lys57Ter 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-val348ile (accessed [today's date]).

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