Is XDH p.Pro214fs (c.641del) pathogenic?

XDH p.Pro214fs (c.641del) is classified Pathogenic in XDH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00704%, nfe); Associated with XDH-related disorder.

What condition is associated with XDH p.Pro214fs (c.641del)?

XDH p.Pro214fs (c.641del) is associated with XDH-related disorder, xanthinuria type I, xanthinuria type II (ClinVar).

How common is XDH p.Pro214fs (c.641del) in the general population?

XDH p.Pro214fs (c.641del) is very rare (popmax 0.00704%, nfe) (gnomAD).

XDH p.Pro214fs

c.641del · rs778685046 · VCV1457782

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00704%, nfe)

Conditions

XDH-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.2	GERP -3.4
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00704% European (non-Finnish) · 82/1,164,228 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00532%

Overall 0.0055% 87/1,582,120 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00704%	14,198
Finnishnot grpmax-eligible	0.00646%	15,471
Remaining individualsnot grpmax-eligible	0.00163%	61,482

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.Pro214fs
Coding: c.641del
MANE Select: NM_003104 · reported on NM_000379
dbSNP: rs778685046
Type: Deletion
Location: chr2:31387821 (GRCh38)
Structure: AlphaFold pLDDT 98.06 · 3 PDB
Residue 214: 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

XDH-related disorder

Also linked: xanthinuria type I xanthinuria type II

Similar variants

XDH p.Glu760fs Pathogenic ★★ same condition
XDH c.2100+19_2100+22del Benign/Likely benign ★★ same condition
XDH c.1242_1242+6del Likely pathogenic ★ same condition
XDH p.Gln919fs Pathogenic ★ same condition
XDH p.Glu448fs Pathogenic ★ same condition
XDH p.Glu45fs Pathogenic ★ same condition
XDH p.Gly1170fs Pathogenic ★ same condition
XDH p.Ile1238fs 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-pro214fs (accessed [today's date]).

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