Is TYK2 p.Phe672= (c.2016C>T) pathogenic?

TYK2 p.Phe672= (c.2016C>T) is classified Likely benign in TYK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-06-10). Ultra-rare (popmax 0.0122%, eas); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Phe672= (c.2016C>T)?

TYK2 p.Phe672= (c.2016C>T) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Phe672= (c.2016C>T) in the general population?

TYK2 p.Phe672= (c.2016C>T) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

TYK2 p.Phe672=

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.2016C>T · rs1019896036 · VCV2197875

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

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	GERP -1.8
Overall
CADD	7.094	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% East Asian · 5/41,004 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00391%

Overall 0.00633% 98/1,547,346 alleles · ultra-rare exomes 89/1,395,358 · genomes 9/151,988 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.034%	2,941
East Asiangrpmax	0.0122%	8,201
Remaining individualsnot grpmax-eligible	0.00666%	15,019
South Asian	0.00595%	16,814
Admixed American	0.00589%	16,976
European (non-Finnish)	0.00541%	18,498

Finnish 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.Phe672=
Coding: c.2016C>T
MANE Select: NM_003331
dbSNP: rs1019896036
Type: single nucleotide variant
Location: chr19:10361542 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 672: the protein kinase 1 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-phe672 (accessed [today's date]).

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