Is TYK2 p.Arg4Pro (c.11G>C) pathogenic?

TYK2 p.Arg4Pro (c.11G>C) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1135); Very rare (popmax 0.00834%, amr); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Arg4Pro (c.11G>C)?

TYK2 p.Arg4Pro (c.11G>C) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Arg4Pro (c.11G>C) in the general population?

TYK2 p.Arg4Pro (c.11G>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about TYK2 p.Arg4Pro (c.11G>C)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

TYK2 p.Arg4Pro

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.11G>C · rs12720343 · VCV1520254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	14.72	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 0.00834% Admixed American · 5/59,956 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000683% 11/1,610,588 alleles · very rare exomes 10/1,458,464 · genomes 1/152,124 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,991
European (non-Finnish)	0.000509%	196,644

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.Arg4Pro
Coding: c.11G>C
MANE Select: NM_003331
dbSNP: rs12720343
Type: single nucleotide variant
Location: chr19:10378396 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 4: a UniProt-annotated variant site (in)

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.Arg4Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TYK2 p.Arg4His Uncertain significance ★ ⚠ same residue
TYK2 p.Arg4= 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

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-arg4pro (accessed [today's date]).

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