Is TYK2 p.Ile93Phe (c.277A>T) pathogenic?

TYK2 p.Ile93Phe (c.277A>T) is classified Uncertain significance in TYK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-23). AlphaMissense: likely benign (0.0934); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Ile93Phe (c.277A>T)?

TYK2 p.Ile93Phe (c.277A>T) is associated with Inborn genetic diseases, immunodeficiency 35 (ClinVar).

How common is TYK2 p.Ile93Phe (c.277A>T) in the general population?

TYK2 p.Ile93Phe (c.277A>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about TYK2 p.Ile93Phe (c.277A>T)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

TYK2 p.Ile93Phe

c.277A>T · rs1434718123 · VCV1023435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -5.66	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 -1.1	GERP -3.6
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	14.97	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,848 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,894 alleles · very rare

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.Ile93Phe
Coding: c.277A>T
MANE Select: NM_003331
dbSNP: rs1434718123
Type: single nucleotide variant
Location: chr19:10368335 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 93: the ferm domain; a turn

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-ile93phe (accessed [today's date]).

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