Is TYK2 p.Pro626Ser (c.1876C>T) pathogenic?

TYK2 p.Pro626Ser (c.1876C>T) is classified Uncertain significance in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.0653); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Pro626Ser (c.1876C>T)?

TYK2 p.Pro626Ser (c.1876C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TYK2 p.Pro626Ser (c.1876C>T) in the general population?

TYK2 p.Pro626Ser (c.1876C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TYK2 p.Pro626Ser (c.1876C>T)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

TYK2 p.Pro626Ser

c.1876C>T · VCV3976426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.26	GERP -2.7
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	2.837	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TYK2
Protein: p.Pro626Ser
Coding: c.1876C>T
MANE Select: NM_003331
Type: single nucleotide variant
Location: chr19:10361853 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 626: the protein kinase 1 domain; the 'disordered' region

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

Similar variants

TYK2 p.Pro626His Uncertain significance ★★ ⚠ same residue
TYK2 p.Pro626= Likely benign ★ same residue
TYK2 p.Ala1026Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala428Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala567Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala671Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Arg269His Uncertain significance ★★ ⚠ same condition
TYK2 p.Arg274Cys 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-pro626ser (accessed [today's date]).

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