Is XDH p.Thr1069Ser (c.3206C>G) pathogenic?

XDH p.Thr1069Ser (c.3206C>G) is classified Uncertain significance in XDH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-05). AlphaMissense: likely benign (0.2287); Very rare (popmax 0.00167%, amr); Associated with xanthinuria type II.

What condition is associated with XDH p.Thr1069Ser (c.3206C>G)?

XDH p.Thr1069Ser (c.3206C>G) is associated with xanthinuria type II, xanthinuria type I (ClinVar).

How common is XDH p.Thr1069Ser (c.3206C>G) in the general population?

XDH p.Thr1069Ser (c.3206C>G) is very rare (popmax 0.00167%, 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.Thr1069Ser (c.3206C>G)?

AlphaMissense predicts likely benign (score 0.2287) — an in-silico prediction, not a clinical call.

XDH p.Thr1069Ser

c.3206C>G · rs1685335731 · VCV1003257

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xanthinuria type II

Computational evidence

Protein change
AlphaMissense	0.2287	likely benign
REVEL	0.62	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	26.7	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 0.00167% Admixed American · 1/60,028 alleles

Overall 6.84e-05% 1/1,461,882 alleles · very rare

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.Thr1069Ser
Coding: c.3206C>G
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs1685335731
Type: single nucleotide variant
Location: chr2:31347592 (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.Thr1069Ala 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
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-thr1069ser (accessed [today's date]).

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