Is TYK2 p.Ala1045fs (c.3133_3142del) pathogenic?

TYK2 p.Ala1045fs (c.31333142del) is classified Pathogenic in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). Very rare (popmax 0.00017%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Ala1045fs (c.3133_3142del)?

TYK2 p.Ala1045fs (c.3133_3142del) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Ala1045fs (c.3133_3142del) in the general population?

TYK2 p.Ala1045fs (c.3133_3142del) is very rare (popmax 0.00017%, nfe) (gnomAD).

TYK2 p.Ala1045fs

Q: How is Susceptibility to infection due to TYK2 deficiency inherited?

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

c.3133_3142del · VCV4803568

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

immunodeficiency 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,176,170 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,454,334 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: TYK2
Protein: p.Ala1045fs
Coding: c.3133_3142del
MANE Select: NM_003331
Type: Deletion
Location: chr19:10352984 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 1045: the protein kinase 2 domain

Full TYK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 35 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Susceptibility to infection due to TYK2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TYK2 p.Cys70fs Pathogenic ★★ same condition
TYK2 p.Pro216fs Pathogenic/Likely pathogenic ★★ same condition
TYK2 p.Leu791_Ser792del Uncertain significance ★★ same condition
TYK2 c.1001_1011+4del Likely pathogenic ★ same condition
TYK2 c.2176-32_2205del Likely pathogenic ★ same condition
TYK2 p.Asp302fs Pathogenic ★ same condition
TYK2 p.Gly1043_Leu1044insTer Pathogenic ★ same condition
TYK2 p.Leu974fs 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/tyk2-p-ala1045fs (accessed [today's date]).

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