Is XDH p.Pro155Thr (c.463C>A) pathogenic?

XDH p.Pro155Thr (c.463C>A) is classified Uncertain significance in XDH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-09). AlphaMissense: ambiguous (0.4831); Rare (popmax 0.107%, afr); Associated with xanthinuria type II.

What condition is associated with XDH p.Pro155Thr (c.463C>A)?

XDH p.Pro155Thr (c.463C>A) is associated with xanthinuria type II, xanthinuria type I (ClinVar).

How common is XDH p.Pro155Thr (c.463C>A) in the general population?

XDH p.Pro155Thr (c.463C>A) is rare (popmax 0.107%, afr) (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.Pro155Thr (c.463C>A)?

AlphaMissense predicts ambiguous (score 0.4831) — an in-silico prediction, not a clinical call.

XDH p.Pro155Thr

c.463C>A · rs145413551 · VCV649230

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4831 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, afr)

Conditions

xanthinuria type II

Computational evidence

Protein change
AlphaMissense	0.4831	ambiguous
REVEL	0.521	indeterminate
SaProt	LLR -14.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.26, phastCons 1
Overall
CADD	22.9	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 0.107% African / African-American · 80/75,052 alleles

Filtering AF 0.0877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0808%

Overall 0.00619% 100/1,614,220 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.107%	938
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.0117%	8,574
European (non-Finnish)	0.000339%	295,010

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.Pro155Thr
Coding: c.463C>A
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs145413551
Type: single nucleotide variant
Location: chr2:31397700 (GRCh38)
Structure: AlphaFold pLDDT 98.06 · 3 PDB
Residue 155: a UniProt-annotated variant site (in hmnr8); an α-helix

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 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
XDH p.Lys722Ter 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-pro155thr (accessed [today's date]).

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