Is XDH p.Val121Ile (c.361G>A) pathogenic?

XDH p.Val121Ile (c.361G>A) is classified Uncertain significance in XDH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-08). AlphaMissense: likely benign (0.123); Ultra-rare (popmax 0.0164%, mid); Associated with xanthinuria type II.

What condition is associated with XDH p.Val121Ile (c.361G>A)?

XDH p.Val121Ile (c.361G>A) is associated with xanthinuria type II, xanthinuria type I (ClinVar).

How common is XDH p.Val121Ile (c.361G>A) in the general population?

XDH p.Val121Ile (c.361G>A) is ultra-rare (popmax 0.0164%, mid) (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.Val121Ile (c.361G>A)?

AlphaMissense predicts likely benign (score 0.123) — an in-silico prediction, not a clinical call.

XDH p.Val121Ile

c.361G>A · rs751332444 · VCV576475

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xanthinuria type II

Computational evidence

Protein change
AlphaMissense	0.123	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -8.47	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 4.8	GERP 2, phastCons 1
Overall
CADD	25.2	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.0026% 42/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00934%	10,704
Admixed American	0.00667%	15,002
European (non-Finnish)	0.00229%	43,703
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,080

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.Val121Ile
Coding: c.361G>A
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs751332444
Type: single nucleotide variant
Location: chr2:31398645 (GRCh38)
Structure: AlphaFold pLDDT 98.06 · 3 PDB
Residue 121: a UniProt-annotated variant site (in hmnr8)

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

SORD p.Ala121Pro Likely pathogenic 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-val121ile (accessed [today's date]).

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