Is TYK2 p.Leu529Phe (c.1585C>T) pathogenic?

TYK2 p.Leu529Phe (c.1585C>T) is classified Uncertain significance in TYK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-03). AlphaMissense: ambiguous (0.4017); Very rare (popmax 0.00347%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Leu529Phe (c.1585C>T)?

TYK2 p.Leu529Phe (c.1585C>T) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Leu529Phe (c.1585C>T) in the general population?

TYK2 p.Leu529Phe (c.1585C>T) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about TYK2 p.Leu529Phe (c.1585C>T)?

AlphaMissense predicts ambiguous (score 0.4017) — an in-silico prediction, not a clinical call.

TYK2 p.Leu529Phe

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.1585C>T · rs375614264 · VCV958341

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.4017	ambiguous
REVEL	0.295	indeterminate
SaProt	LLR -9.56	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.55, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	23.6	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 0.00347% European (non-Finnish) · 41/1,180,012 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.0026% 42/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,781
Finnishnot grpmax-eligible	0.00156%	64,022

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.Leu529Phe
Coding: c.1585C>T
MANE Select: NM_003331
dbSNP: rs375614264
Type: single nucleotide variant
Location: chr19:10362348 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 529: the sh2; atypical 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.Leu529= 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-leu529phe (accessed [today's date]).

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