Is TYK2 p.Pro1105His (c.3314C>A) pathogenic?

TYK2 p.Pro1105His (c.3314C>A) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.6115); No allele count reported in gnomAD v4.1 (AN 1,606,860); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Pro1105His (c.3314C>A)?

TYK2 p.Pro1105His (c.3314C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TYK2 p.Pro1105His (c.3314C>A) in the general population?

TYK2 p.Pro1105His (c.3314C>A) is no allele count reported in gnomAD v4.1 (AN 1,606,860) (gnomAD).

What do computational predictors say about TYK2 p.Pro1105His (c.3314C>A)?

AlphaMissense predicts likely pathogenic (score 0.6115) — an in-silico prediction, not a clinical call.

TYK2 p.Pro1105His

c.3314C>A · VCV4633995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6115 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,606,860)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6115	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	22.9	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

No allele count reported in gnomAD v4.1 (AN 1,606,860). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TYK2
Protein: p.Pro1105His
Coding: c.3314C>A
MANE Select: NM_003331
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.Pro1105Arg 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-pro1105his (accessed [today's date]).

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