Is XIAP p.Pro374= (c.1122T>C) pathogenic?

XIAP p.Pro374= (c.1122T>C) is classified Benign in XIAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). Ultra-rare (popmax 0.0227%, afr); Associated with X-linked lymphoproliferative disease due to XIAP deficiency.

What condition is associated with XIAP p.Pro374= (c.1122T>C)?

XIAP p.Pro374= (c.1122T>C) is associated with X-linked lymphoproliferative disease due to XIAP deficiency (ClinVar).

How common is XIAP p.Pro374= (c.1122T>C) in the general population?

XIAP p.Pro374= (c.1122T>C) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

XIAP p.Pro374=

Q: How is X-linked lymphoproliferative disease due to XIAP deficiency inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1122T>C · rs141902336 · VCV2067973

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

X-linked lymphoproliferative disease due to XIAP deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP -0.79, phastCons 1
Overall
CADD	7.978	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 13/57,238 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00132% 16/1,208,798 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,403
Remaining individualsnot grpmax-eligible	0.00631%	15,851

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: XIAP
Protein: p.Pro374=
Coding: c.1122T>C
MANE Select: NM_001167
dbSNP: rs141902336
Type: single nucleotide variant
Location: chrX:123900515 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 74 PDB
Residue 374: a UniProt-annotated variant site (in xlp2; uncertain significance)

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

Disease context

X-linked lymphoproliferative disease due to XIAP deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked lymphoproliferative disease due to XIAP deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

XIAP p.Pro374Ser Uncertain significance ★ ⚠ same residue
XIAP p.Arg222Ter Pathogenic ★★ same condition
XIAP p.Arg381Ter Pathogenic ★★ same condition
XIAP p.Glu337Ter Pathogenic ★★ same condition
XIAP p.His220Tyr Likely pathogenic ★★ same condition
XIAP p.Tyr115Ter Pathogenic ★★ same condition
XIAP p.Ala137Gly Uncertain significance ★★ ⚠ same condition
XIAP p.Ala68Val Uncertain significance ★★ ⚠ 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/xiap-p-pro374 (accessed [today's date]).

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