Is TYK2 p.Pro681Ser (c.2041C>T) pathogenic?

TYK2 p.Pro681Ser (c.2041C>T) is classified Conflicting classifications of pathogenicity in TYK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-08). AlphaMissense: likely benign (0.0583); Very rare (popmax 0.00323%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Pro681Ser (c.2041C>T)?

TYK2 p.Pro681Ser (c.2041C>T) is associated with Inborn genetic diseases, immunodeficiency 35 (ClinVar).

How common is TYK2 p.Pro681Ser (c.2041C>T) in the general population?

TYK2 p.Pro681Ser (c.2041C>T) is very rare (popmax 0.00323%, nfe) (gnomAD).

What do computational predictors say about TYK2 p.Pro681Ser (c.2041C>T)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

TYK2 p.Pro681Ser

c.2041C>T · rs1433952909 · VCV952319

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00323%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0583	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.93	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 4.4	GERP -3.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	9.088	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 0.00323% European (non-Finnish) · 37/1,146,830 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.00259% 40/1,545,362 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00323%	30,995
East Asian	0.00244%	40,938
Admixed American	0.00196%	50,926
African / African-American	0.00137%	72,942

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.Pro681Ser
Coding: c.2041C>T
MANE Select: NM_003331
dbSNP: rs1433952909
Type: single nucleotide variant
Location: chr19:10361517 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 681: the protein kinase 1 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.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
TYK2 p.Ala413Val 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-pro681ser (accessed [today's date]).

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