Is TYK2 p.Thr172= (c.516C>T) pathogenic?

TYK2 p.Thr172= (c.516C>T) is classified Benign in TYK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 17.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Thr172= (c.516C>T)?

TYK2 p.Thr172= (c.516C>T) is associated with immunodeficiency 35 (ClinVar).

TYK2 p.Thr172=

Q: How common is TYK2 p.Thr172= (c.516C>T) in the general population?

TYK2 p.Thr172= (c.516C>T) is common (popmax 17.8%, afr) — 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.516C>T · rs280523 · VCV137863

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 17.8%, afr) — too common for a highly-penetrant pathogenic allele

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 -5.7	GERP -3.6
Overall
CADD	0.457	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 17.8% African / African-American · 13,307/74,910 alleles

Filtering AF 17.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.4%

Overall 7.63% 123,057/1,613,758 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	17.8%	6
Finnishnot grpmax-eligible	11.5%	9
Remaining individualsnot grpmax-eligible	7.42%	13
Amishnot grpmax-eligible	7.36%	14
European (non-Finnish)	7.22%	14
South Asian	6.78%	15
Middle Eastern	5.39%	19
Admixed American	4.53%	22
East Asian	4.42%	23
Ashkenazi Jewishnot grpmax-eligible	4.38%	23

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.Thr172=
Coding: c.516C>T
MANE Select: NM_003331
dbSNP: rs280523
Type: single nucleotide variant
Location: chr19:10366530 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 172: the ferm domain

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-thr172 (accessed [today's date]).

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