Is TYK2 p.Leu403Val (c.1207C>G) pathogenic?

TYK2 p.Leu403Val (c.1207C>G) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13). AlphaMissense: likely benign (0.1743); Very rare (popmax 0.00133%, afr); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Leu403Val (c.1207C>G)?

TYK2 p.Leu403Val (c.1207C>G) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Leu403Val (c.1207C>G) in the general population?

TYK2 p.Leu403Val (c.1207C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TYK2 p.Leu403Val (c.1207C>G)?

AlphaMissense predicts likely benign (score 0.1743) — an in-silico prediction, not a clinical call.

TYK2 p.Leu403Val

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.1207C>G · rs774318353 · VCV851330

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.1743	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.94	donor gain · deltas
Pangolin	Δ0.77	gain · loss 0.27 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP -0.13, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	27.5	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 0.00133% African / African-American · 1/74,958 alleles

Overall 0.000657% 1/152,286 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.Leu403Val
Coding: c.1207C>G
MANE Select: NM_003331
dbSNP: rs774318353
Type: single nucleotide variant
Location: chr19:10364853 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 403: the ferm 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.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-leu403val (accessed [today's date]).

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