Is TYK2 p.Ile684Ser (c.2051T>G) pathogenic?

TYK2 p.Ile684Ser (c.2051T>G) is classified Benign/Likely benign in TYK2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.5863); Common (popmax 9.37%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Ile684Ser (c.2051T>G)?

TYK2 p.Ile684Ser (c.2051T>G) is associated with immunodeficiency 35 (ClinVar).

What do computational predictors say about TYK2 p.Ile684Ser (c.2051T>G)?

AlphaMissense predicts likely pathogenic (score 0.5863) — an in-silico prediction, not a clinical call.

TYK2 p.Ile684Ser

Q: How common is TYK2 p.Ile684Ser (c.2051T>G) in the general population?

TYK2 p.Ile684Ser (c.2051T>G) is common (popmax 9.37%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Susceptibility to infection due to TYK2 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2051T>G · rs12720356 · VCV259043

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5863 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.37%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.5863	likely pathogenic
REVEL	0.343	indeterminate
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.86	acceptor gain · deltas
Pangolin	Δ0.27	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.1	GERP 0.41, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	34.0	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 9.37% European (non-Finnish) · 110,559/1,179,728 alleles

Filtering AF 9.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.31%

Overall 7.97% 128,313/1,610,644 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	10%	10
European (non-Finnish)grpmax	9.37%	11
Finnishnot grpmax-eligible	8.33%	12
Remaining individualsnot grpmax-eligible	7.67%	13
Middle Eastern	5.81%	17
Amishnot grpmax-eligible	5.04%	20
Admixed American	4.26%	23
African / African-American	1.41%	71
South Asian	0.989%	101
East Asian	0.0156%	6,409

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile684Ser
Coding: c.2051T>G
MANE Select: NM_003331
dbSNP: rs12720356
Type: single nucleotide variant
Location: chr19:10359299 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 684: a UniProt-annotated variant site (in); the protein kinase 1 domain; a β-strand

Full TYK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 35 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Susceptibility to infection due to TYK2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TYK2 p.Ile684= Likely benign ★ 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-ile684ser (accessed [today's date]).

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