Is TYK2 p.Ala412= (c.1236G>A) pathogenic?

TYK2 p.Ala412= (c.1236G>A) is classified Conflicting classifications of pathogenicity in TYK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-28). Ultra-rare (popmax 0.0214%, nfe); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Ala412= (c.1236G>A)?

TYK2 p.Ala412= (c.1236G>A) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Ala412= (c.1236G>A) in the general population?

TYK2 p.Ala412= (c.1236G>A) is ultra-rare (popmax 0.0214%, nfe) (gnomAD).

TYK2 p.Ala412=

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.1236G>A · rs56212434 · VCV739904

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, nfe)

Conditions

immunodeficiency 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.009	strongly benign-leaning
Splicing
SpliceAI	Δ0.83	acceptor gain · deltas
Pangolin	Δ0.67	gain · loss 0.26 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -6	GERP -4.5
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% European (non-Finnish) · 252/1,179,994 alleles

Filtering AF 0.0192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0183%

Overall 0.0163% 263/1,613,804 alleles · ultra-rare exomes 242/1,461,574 · genomes 21/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0214%	4,683
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.004%	24,981
Finnishnot grpmax-eligible	0.00157%	63,802

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.Ala412=
Coding: c.1236G>A
MANE Select: NM_003331
dbSNP: rs56212434
Type: single nucleotide variant
Location: chr19:10364745 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 412: the ferm 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.Ala412Val Uncertain significance ★ ⚠ same residue
TYK2 p.Ala412Gly Uncertain significance ★ ⚠ same residue
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

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-ala412 (accessed [today's date]).

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