Is XDH p.Ile703Lys (c.2108T>A) pathogenic?

XDH p.Ile703Lys (c.2108T>A) is classified Uncertain significance in XDH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-13). AlphaMissense: ambiguous (0.3955); Ultra-rare (popmax 0.0387%, afr); Associated with Inborn genetic diseases.

What condition is associated with XDH p.Ile703Lys (c.2108T>A)?

XDH p.Ile703Lys (c.2108T>A) is associated with Inborn genetic diseases, xanthinuria type I, xanthinuria type II (ClinVar).

How common is XDH p.Ile703Lys (c.2108T>A) in the general population?

XDH p.Ile703Lys (c.2108T>A) is ultra-rare (popmax 0.0387%, afr) (gnomAD).

What do computational predictors say about XDH p.Ile703Lys (c.2108T>A)?

AlphaMissense predicts ambiguous (score 0.3955) — an in-silico prediction, not a clinical call.

XDH p.Ile703Lys

c.2108T>A · rs142848703 · VCV3190977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3955	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -12.33	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Overall
CADD	26.1	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 0.0387% African / African-American · 29/74,922 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00204% 33/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0387%	2,584
Admixed American	0.00333%	30,004
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ile703Lys
Coding: c.2108T>A
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs142848703
Type: single nucleotide variant
Location: chr2:31368050 (GRCh38)
Structure: AlphaFold pLDDT 98.06 · 3 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xanthinuria type I xanthinuria type II

Similar variants

XDH p.Ile703Val Benign/Likely benign ★★ ⚠ same residue
SORD p.Ala153Asp Pathogenic/Likely pathogenic ★★ same condition
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-ile703lys (accessed [today's date]).

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