Is TYK2 p.Pro1104Ala (c.3310C>G) pathogenic?

TYK2 p.Pro1104Ala (c.3310C>G) is classified Benign/Likely benign in TYK2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.8292); Low-frequency (popmax 4.45%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Pro1104Ala (c.3310C>G)?

TYK2 p.Pro1104Ala (c.3310C>G) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Pro1104Ala (c.3310C>G) in the general population?

TYK2 p.Pro1104Ala (c.3310C>G) is low-frequency (popmax 4.45%, nfe) (gnomAD).

What do computational predictors say about TYK2 p.Pro1104Ala (c.3310C>G)?

AlphaMissense predicts likely pathogenic (score 0.8292) — an in-silico prediction, not a clinical call.

TYK2 p.Pro1104Ala

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.3310C>G · rs34536443 · VCV137869

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8292 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.45%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.8292	likely pathogenic
REVEL	0.586	indeterminate
SaProt	LLR -10.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.99, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	25.0	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 4.45% European (non-Finnish) · 52,288/1,174,994 alleles

Filtering AF 4.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.4%

Overall 3.71% 59,598/1,607,098 alleles · low-frequency exomes 55,360/1,454,820 · genomes 4,238/152,278 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	4.45%	22
Ashkenazi Jewishnot grpmax-eligible	3.09%	32
Finnishnot grpmax-eligible	2.98%	34
Remaining individualsnot grpmax-eligible	2.95%	34
Middle Eastern	2.02%	49
Admixed American	1.47%	68
Amishnot grpmax-eligible	1.43%	70
South Asian	1.15%	87
African / African-American	0.819%	122
East Asian	0.00223%	44,808

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.Pro1104Ala
Coding: c.3310C>G
MANE Select: NM_003331
dbSNP: rs34536443
Type: single nucleotide variant
Location: chr19:10352442 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 1104: an α-helix; a UniProt-annotated variant site (in); 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.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-pro1104ala (accessed [today's date]).

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