Is TYK2 p.Arg565Gln (c.1694G>A) pathogenic?

TYK2 p.Arg565Gln (c.1694G>A) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-10). AlphaMissense: likely benign (0.0979); Very rare (popmax 0.00668%, eas); Associated with Recurrent skin infections.

What condition is associated with TYK2 p.Arg565Gln (c.1694G>A)?

TYK2 p.Arg565Gln (c.1694G>A) is associated with Recurrent skin infections, immunodeficiency disease (ClinVar).

How common is TYK2 p.Arg565Gln (c.1694G>A) in the general population?

TYK2 p.Arg565Gln (c.1694G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about TYK2 p.Arg565Gln (c.1694G>A)?

AlphaMissense predicts likely benign (score 0.0979) — an in-silico prediction, not a clinical call.

TYK2 p.Arg565Gln

c.1694G>A · rs764267766 · VCV800726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Recurrent skin infections

Computational evidence

Protein change
AlphaMissense	0.0979	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.97	acceptor gain · deltas
Pangolin	Δ0.76	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	35.0	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 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000496% 8/1,613,814 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
South Asian	0.00329%	30,359
European (non-Finnish)	0.000169%	590,002

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.Arg565Gln
Coding: c.1694G>A
MANE Select: NM_003331
dbSNP: rs764267766
Type: single nucleotide variant
Location: chr19:10362157 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 565: a β-strand

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

Disease context

Recurrent skin infections — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency disease

Similar variants

TYK2 p.Pro216= Conflicting classifications of pathogenicity ★ same condition
TYK2 p.Arg609Ter Pathogenic/Likely pathogenic ★★ same type
TYK2 p.Trp798Ter Pathogenic ★★ same type
TYK2 p.Ala1004Gly Uncertain significance ★★ ⚠ same type
TYK2 p.Ala1026Thr Uncertain significance ★★ ⚠ same type
TYK2 p.Ala165Thr Uncertain significance ★★ ⚠ same type
TYK2 p.Ala195Ser Uncertain significance ★★ ⚠ same type
TYK2 p.Ala195Thr Uncertain significance ★★ same type

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-arg565gln (accessed [today's date]).

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