Is TYK2 p.Pro1105Ala (c.3313C>G) pathogenic?

TYK2 p.Pro1105Ala (c.3313C>G) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-20). AlphaMissense: likely benign (0.2464); Very rare (popmax 8.51e-05%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Pro1105Ala (c.3313C>G)?

TYK2 p.Pro1105Ala (c.3313C>G) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Pro1105Ala (c.3313C>G) in the general population?

TYK2 p.Pro1105Ala (c.3313C>G) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about TYK2 p.Pro1105Ala (c.3313C>G)?

AlphaMissense predicts likely benign (score 0.2464) — an in-silico prediction, not a clinical call.

TYK2 p.Pro1105Ala

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.3313C>G · rs764595468 · VCV2013396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.2464	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -0.21, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,298 alleles

Overall 6.22e-05% 1/1,607,566 alleles · very rare exomes 1/1,455,256 · genomes 0/152,310 · joint denominator

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.Pro1105Ala
Coding: c.3313C>G
MANE Select: NM_003331
dbSNP: rs764595468
Type: single nucleotide variant
Location: chr19:10352439 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 1105: an α-helix; the protein kinase 2 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.Pro1105= Likely benign ★ same residue
TYK2 p.Pro1105Arg Uncertain significance ★ ⚠ same residue
TYK2 p.Pro1105His Uncertain significance ★ ⚠ same residue
TYK2 p.Pro1105Ser Uncertain significance ★ 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

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-pro1105ala (accessed [today's date]).

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