Is TYK2 p.Arg370Trp (c.1108C>T) pathogenic?

TYK2 p.Arg370Trp (c.1108C>T) is classified Conflicting classifications of pathogenicity in TYK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.0889); Rare (popmax 0.389%, sas); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Arg370Trp (c.1108C>T)?

TYK2 p.Arg370Trp (c.1108C>T) is associated with Inborn genetic diseases, immunodeficiency 35 (ClinVar).

How common is TYK2 p.Arg370Trp (c.1108C>T) in the general population?

TYK2 p.Arg370Trp (c.1108C>T) is rare (popmax 0.389%, sas) (gnomAD).

What do computational predictors say about TYK2 p.Arg370Trp (c.1108C>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

TYK2 p.Arg370Trp

c.1108C>T · rs550060811 · VCV889613

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.389%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -8.97	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 0.29	GERP -3.9, phastCons 0.001
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	17.44	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 0.389% South Asian · 354/91,090 alleles

Filtering AF 0.355% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.342%

Overall 0.0229% 369/1,614,102 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.389%	257
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00167%	60,030
European (non-Finnish)	0.000169%	590,016

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.Arg370Trp
Coding: c.1108C>T
MANE Select: NM_003331
dbSNP: rs550060811
Type: single nucleotide variant
Location: chr19:10364952 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 370: 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.Arg370Gln 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-arg370trp (accessed [today's date]).

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