Is TYK2 p.Arg679Pro (c.2036G>C) pathogenic?

TYK2 p.Arg679Pro (c.2036G>C) is classified Conflicting classifications of pathogenicity in TYK2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-07-03). AlphaMissense: ambiguous (0.3501); Rare (popmax 0.117%, mid); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Arg679Pro (c.2036G>C)?

TYK2 p.Arg679Pro (c.2036G>C) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Arg679Pro (c.2036G>C) in the general population?

TYK2 p.Arg679Pro (c.2036G>C) is rare (popmax 0.117%, mid) (gnomAD).

What do computational predictors say about TYK2 p.Arg679Pro (c.2036G>C)?

AlphaMissense predicts ambiguous (score 0.3501) — an in-silico prediction, not a clinical call.

TYK2 p.Arg679Pro

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.2036G>C · rs200247986 · VCV838178

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3501 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, mid)

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.3501	ambiguous
REVEL	0.526	indeterminate
SaProt	LLR -11.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -2.1, phastCons 0.68
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	21.8	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 0.117% Middle Eastern · 7/5,970 alleles

Filtering AF 0.055% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0414%

Overall 0.012% 186/1,545,668 alleles · rare exomes 152/1,393,684 · genomes 34/151,984 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.117%	853
Admixed American	0.0648%	1,544
Remaining individualsnot grpmax-eligible	0.025%	4,005
European (non-Finnish)	0.0106%	9,478
Ashkenazi Jewishnot grpmax-eligible	0.0105%	9,546
African / African-American	0.00958%	10,433

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.Arg679Pro
Coding: c.2036G>C
MANE Select: NM_003331
dbSNP: rs200247986
Type: single nucleotide variant
Location: chr19:10361522 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 679: the protein kinase 1 domain; a β-strand

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.Arg679Cys Uncertain significance ★★ ⚠ same residue
TYK2 p.Arg679= Likely benign ★★ same residue
TYK2 p.Arg679His 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
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-arg679pro (accessed [today's date]).

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