Is TYK2 p.Arg269Cys (c.805C>T) pathogenic?

TYK2 p.Arg269Cys (c.805C>T) is classified Conflicting classifications of pathogenicity in TYK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1073); Ultra-rare (popmax 0.0535%, eas); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Arg269Cys (c.805C>T)?

TYK2 p.Arg269Cys (c.805C>T) is associated with Inborn genetic diseases, immunodeficiency 35 (ClinVar).

How common is TYK2 p.Arg269Cys (c.805C>T) in the general population?

TYK2 p.Arg269Cys (c.805C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

What do computational predictors say about TYK2 p.Arg269Cys (c.805C>T)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

TYK2 p.Arg269Cys

c.805C>T · rs368109068 · VCV451636

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.86, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	21.7	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 0.0535% East Asian · 24/44,868 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00508% 82/1,613,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
Finnishnot grpmax-eligible	0.019%	5,272
Middle Eastern	0.0165%	6,062
Admixed American	0.01%	9,993
Remaining individualsnot grpmax-eligible	0.00961%	10,409
African / African-American	0.00266%	37,525
European (non-Finnish)	0.00254%	39,329
South Asian	0.0011%	91,044

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.Arg269Cys
Coding: c.805C>T
MANE Select: NM_003331
dbSNP: rs368109068
Type: single nucleotide variant
Location: chr19:10365723 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 269: the ferm domain; a turn

Full TYK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 35

Similar variants

TYK2 p.Arg269His Uncertain significance ★★ ⚠ same residue
TYK2 p.Arg269Leu 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
TYK2 p.Ala195Ser 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-arg269cys (accessed [today's date]).

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