Is TYK2 p.Ile651= (c.1953C>T) pathogenic?

TYK2 p.Ile651= (c.1953C>T) is classified Benign in TYK2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.62%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Ile651= (c.1953C>T)?

TYK2 p.Ile651= (c.1953C>T) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Ile651= (c.1953C>T) in the general population?

TYK2 p.Ile651= (c.1953C>T) is low-frequency (popmax 1.62%, nfe) (gnomAD).

TYK2 p.Ile651=

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.1953C>T · rs12720355 · VCV259042

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.62%, nfe)

Conditions

immunodeficiency 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -4.3
Overall
CADD	1.767	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.62% European (non-Finnish) · 19,143/1,179,766 alleles

Filtering AF 1.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.6%

Overall 1.36% 21,912/1,612,786 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.87%	35
European (non-Finnish)grpmax	1.62%	62
Finnishnot grpmax-eligible	1.19%	84
Remaining individualsnot grpmax-eligible	1.14%	88
South Asian	0.668%	150
Admixed American	0.592%	169
Ashkenazi Jewishnot grpmax-eligible	0.395%	253
Middle Eastern	0.264%	378
African / African-American	0.237%	422
East Asian	0.00223%	44,802

Amish 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.Ile651=
Coding: c.1953C>T
MANE Select: NM_003331
dbSNP: rs12720355
Type: single nucleotide variant
Location: chr19:10361776 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 651: the protein kinase 1 domain; an α-helix

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.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-ile651 (accessed [today's date]).

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