Is TYK2 p.Pro1105Arg (c.3314C>G) pathogenic?

TYK2 p.Pro1105Arg (c.3314C>G) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.5841); Ultra-rare (popmax 0.0112%, eas); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Pro1105Arg (c.3314C>G)?

TYK2 p.Pro1105Arg (c.3314C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TYK2 p.Pro1105Arg (c.3314C>G) in the general population?

TYK2 p.Pro1105Arg (c.3314C>G) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about TYK2 p.Pro1105Arg (c.3314C>G)?

AlphaMissense predicts likely pathogenic (score 0.5841) — an in-silico prediction, not a clinical call.

TYK2 p.Pro1105Arg

c.3314C>G · rs2040858677 · VCV3185238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5841	likely pathogenic
REVEL	0.376	indeterminate
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP -1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	24.1	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 0.0112% East Asian · 5/44,794 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000373% 6/1,606,862 alleles · ultra-rare exomes 6/1,454,554 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,959
European (non-Finnish)	8.51e-05%	1,174,593

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.Pro1105Arg
Coding: c.3314C>G
MANE Select: NM_003331
dbSNP: rs2040858677
Type: single nucleotide variant
Location: chr19:10352438 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 1105: an α-helix; the protein kinase 2 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

Similar variants

TYK2 p.Pro1105His Uncertain significance ★ ⚠ same residue
TYK2 p.Pro1105Ala Uncertain significance ★ ⚠ same residue
TYK2 p.Pro1105Ser Uncertain significance ★ same residue
TYK2 p.Pro1105= Likely benign ★ same residue
TYK2 p.Ala1026Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala428Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala567Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala671Thr 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-pro1105arg (accessed [today's date]).

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