Is XIAP p.Phe92= (c.276T>C) pathogenic?

XIAP p.Phe92= (c.276T>C) is classified Benign/Likely benign in XIAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-13). Rare (popmax 0.154%, nfe); Associated with X-linked lymphoproliferative disease due to XIAP deficiency.

What condition is associated with XIAP p.Phe92= (c.276T>C)?

XIAP p.Phe92= (c.276T>C) is associated with X-linked lymphoproliferative disease due to XIAP deficiency (ClinVar).

How common is XIAP p.Phe92= (c.276T>C) in the general population?

XIAP p.Phe92= (c.276T>C) is rare (popmax 0.154%, nfe) (gnomAD).

XIAP p.Phe92=

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.276T>C · rs45575532 · VCV533657

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.154%, nfe)

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 6.2	GERP 1.9, phastCons 1
Overall
CADD	11.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.154% European (non-Finnish) · 1,382/895,301 alleles

Filtering AF 0.148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.121% 1,465/1,210,110 alleles · rare exomes 1,375/1,098,251 · genomes 90/111,859 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.154%	648
Remaining individualsnot grpmax-eligible	0.0987%	1,014
African / African-American	0.0384%	2,603
Admixed American	0.0153%	6,515
Finnishnot grpmax-eligible	0.0107%	9,314
Ashkenazi Jewishnot grpmax-eligible	0.00908%	11,017

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.Phe92=
Coding: c.276T>C
MANE Select: NM_001167
dbSNP: rs45575532
Type: single nucleotide variant
Location: chrX:123885938 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 74 PDB
Residue 92: a turn

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.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
XIAP p.Ala79Thr 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-phe92 (accessed [today's date]).

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