Is TYK2 p.Arg294Trp (c.880C>T) pathogenic?

TYK2 p.Arg294Trp (c.880C>T) is classified Uncertain significance in TYK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-30). AlphaMissense: likely benign (0.0812); Ultra-rare (popmax 0.0267%, amr); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Arg294Trp (c.880C>T)?

TYK2 p.Arg294Trp (c.880C>T) is associated with Inborn genetic diseases, immunodeficiency 35 (ClinVar).

How common is TYK2 p.Arg294Trp (c.880C>T) in the general population?

TYK2 p.Arg294Trp (c.880C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about TYK2 p.Arg294Trp (c.880C>T)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

TYK2 p.Arg294Trp

c.880C>T · rs367656874 · VCV2373248

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -7.77	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 0.62	GERP -0.45
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	21.3	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 0.0267% Admixed American · 16/59,984 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00161% 26/1,613,532 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,749
Finnishnot grpmax-eligible	0.00471%	21,251
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,576
European (non-Finnish)	0.000509%	196,642

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.Arg294Trp
Coding: c.880C>T
MANE Select: NM_003331
dbSNP: rs367656874
Type: single nucleotide variant
Location: chr19:10365648 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 294: the ferm domain

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.Arg294Gln 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
TYK2 p.Ala195Thr 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-arg294trp (accessed [today's date]).

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