Is TYK2 p.Ser418Ter (c.1253C>A) pathogenic?

TYK2 p.Ser418Ter (c.1253C>A) is classified Pathogenic in TYK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-02). Very rare (popmax 8.47e-05%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Ser418Ter (c.1253C>A)?

TYK2 p.Ser418Ter (c.1253C>A) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Ser418Ter (c.1253C>A) in the general population?

TYK2 p.Ser418Ter (c.1253C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

TYK2 p.Ser418Ter

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.1253C>A · rs759111483 · VCV1703749

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

immunodeficiency 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 25
REVEL	0.445	indeterminate
Splicing
SpliceAI	Δ0.71	acceptor gain · deltas
Pangolin	Δ0.32	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Overall
CADD	47.0	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.84e-05% 1/1,461,498 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.Ser418Ter
Coding: c.1253C>A
MANE Select: NM_003331
dbSNP: rs759111483
Type: single nucleotide variant
Location: chr19:10364728 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 418: the ferm domain; an α-helix

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.Ser418= Conflicting classifications of pathogenicity ★ same residue
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

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-ser418ter (accessed [today's date]).

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