Is TYK2 p.Ala413Val (c.1238C>T) pathogenic?

TYK2 p.Ala413Val (c.1238C>T) is classified Uncertain significance in TYK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-25). AlphaMissense: ambiguous (0.3894); Ultra-rare (popmax 0.0667%, afr); Associated with immunodeficiency 35.

What condition is associated with TYK2 p.Ala413Val (c.1238C>T)?

TYK2 p.Ala413Val (c.1238C>T) is associated with immunodeficiency 35 (ClinVar).

How common is TYK2 p.Ala413Val (c.1238C>T) in the general population?

TYK2 p.Ala413Val (c.1238C>T) is ultra-rare (popmax 0.0667%, afr) (gnomAD).

What do computational predictors say about TYK2 p.Ala413Val (c.1238C>T)?

AlphaMissense predicts ambiguous (score 0.3894) — an in-silico prediction, not a clinical call.

TYK2 p.Ala413Val

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.1238C>T · rs138661716 · VCV648900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3894 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, afr)

Conditions

immunodeficiency 35

Computational evidence

Protein change
AlphaMissense	0.3894	ambiguous
REVEL	0.489	indeterminate
SaProt	LLR -9.29	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0667% African / African-American · 50/74,952 alleles

Filtering AF 0.052% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0467%

Overall 0.00551% 89/1,613,790 alleles · ultra-rare exomes 63/1,461,554 · genomes 26/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0667%	1,499
European (non-Finnish)	0.00322%	31,053
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Ala413Val
Coding: c.1238C>T
MANE Select: NM_003331
dbSNP: rs138661716
Type: single nucleotide variant
Location: chr19:10364743 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 413: 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.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.Ala428Thr 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-ala413val (accessed [today's date]).

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