Is TYK2 p.Phe514= (c.1542C>T) pathogenic?

TYK2 p.Phe514= (c.1542C>T) is classified Likely benign in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Ultra-rare (popmax 0.0111%, eas); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Phe514= (c.1542C>T)?

TYK2 p.Phe514= (c.1542C>T) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Phe514= (c.1542C>T) in the general population?

TYK2 p.Phe514= (c.1542C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

TYK2 p.Phe514=

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.1542C>T · rs773294079 · VCV1141980

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

immunodeficiency 35

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 0.041	GERP -3.3
Overall
CADD	2.796	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00291% 47/1,613,688 alleles · ultra-rare exomes 44/1,461,504 · genomes 3/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
European (non-Finnish)	0.00314%	31,889
African / African-American	0.00267%	37,463
South Asian	0.0022%	45,524
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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.Phe514=
Coding: c.1542C>T
MANE Select: NM_003331
dbSNP: rs773294079
Type: single nucleotide variant
Location: chr19:10362391 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 514: the sh2; atypical domain; a β-strand

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-phe514 (accessed [today's date]).

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