Is TYK2 p.Pro454= (c.1362C>G) pathogenic?

TYK2 p.Pro454= (c.1362C>G) is classified Likely benign in TYK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-26). Ultra-rare (popmax 0.0494%, mid); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Pro454= (c.1362C>G)?

TYK2 p.Pro454= (c.1362C>G) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Pro454= (c.1362C>G) in the general population?

TYK2 p.Pro454= (c.1362C>G) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

TYK2 p.Pro454=

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.1362C>G · rs374268170 · VCV743841

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Conditions

immunodeficiency 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.224	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -2.9, phastCons 0.11
Overall
CADD	2.672	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,076 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00403% 65/1,613,606 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
South Asian	0.00988%	10,121
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.0039%	25,652
Admixed American	0.00333%	29,996
East Asian	0.00223%	44,896

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.Pro454=
Coding: c.1362C>G
MANE Select: NM_003331
dbSNP: rs374268170
Type: single nucleotide variant
Location: chr19:10364619 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 454: the sh2; atypical 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.Arg609Ter Pathogenic/Likely pathogenic ★★ same condition
TYK2 p.Trp798Ter Pathogenic ★★ same condition
TYK2 p.Ala1004Gly Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala1026Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala165Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala195Thr Uncertain significance ★★ same condition
TYK2 p.Ala413Val 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/tyk2-p-pro454 (accessed [today's date]).

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