Is TYK2 p.Val362Phe (c.1084G>T) pathogenic?

TYK2 p.Val362Phe (c.1084G>T) is classified Benign/Likely benign in TYK2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0829); Common (popmax 45.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Val362Phe (c.1084G>T)?

TYK2 p.Val362Phe (c.1084G>T) is associated with immunodeficiency 35 (ClinVar).

What do computational predictors say about TYK2 p.Val362Phe (c.1084G>T)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

TYK2 p.Val362Phe

Q: How common is TYK2 p.Val362Phe (c.1084G>T) in the general population?

TYK2 p.Val362Phe (c.1084G>T) is common (popmax 45.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1084G>T · rs2304256 · VCV259040

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 45.3%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.17	GERP -2
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	7.337	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 45.3% East Asian · 20,309/44,854 alleles

Filtering AF 44.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 44.5%

Overall 27.6% 446,002/1,613,710 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	45.3%	2
Amishnot grpmax-eligible	41.5%	2
Ashkenazi Jewishnot grpmax-eligible	30.8%	3
Remaining individualsnot grpmax-eligible	28.8%	3
European (non-Finnish)	28.5%	4
Middle Eastern	28.3%	4
South Asian	26.4%	4
Finnishnot grpmax-eligible	24.6%	4
Admixed American	20.9%	5
African / African-American	10.7%	9

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.Val362Phe
Coding: c.1084G>T
MANE Select: NM_003331
dbSNP: rs2304256
Type: single nucleotide variant
Location: chr19:10364976 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 362: the ferm domain; a UniProt-annotated variant site (in); the 'disordered' region

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.Val362= Likely benign ★ 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-val362phe (accessed [today's date]).

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