Is TYROBP p.Ser20Ile (c.59G>T) pathogenic?

TYROBP p.Ser20Ile (c.59G>T) is classified Uncertain significance in TYROBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely benign (0.1926); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TYROBP p.Ser20Ile (c.59G>T)?

TYROBP p.Ser20Ile (c.59G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TYROBP p.Ser20Ile (c.59G>T) in the general population?

TYROBP p.Ser20Ile (c.59G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TYROBP p.Ser20Ile (c.59G>T)?

AlphaMissense predicts likely benign (score 0.1926) — an in-silico prediction, not a clinical call.

TYROBP p.Ser20Ile

c.59G>T · VCV3812660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1926 · 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	0.1926	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.96	donor loss · deltas
Constraint at this position
Conservation	phyloP 0.43	GERP -3.7, phastCons 0.001
Regional constraint	o/e 1.06	unconstrained · MANE · 3,656 bp · p 0.43 · regional, not allelic
Overall
CADD	17.9	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: TYROBP
Protein: p.Ser20Ile
Coding: c.59G>T
MANE Select: NM_003332
Type: single nucleotide variant
Location: chr19:35908170 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.10 · 5 PDB

Full TYROBP 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

TYROBP p.Ser20Gly Uncertain significance ★ ⚠ same residue
TYROBP p.Ala44Thr Uncertain significance ★★ ⚠ same condition
TYROBP p.Arg70Trp Uncertain significance ★★ ⚠ same condition
TYROBP p.Asp104Asn Uncertain significance ★★ ⚠ same condition
TYROBP p.Pro40Leu Uncertain significance ★★ same condition
TYROBP p.Ser99Leu Uncertain significance ★★ ⚠ same condition
TYROBP p.Val38Met Uncertain significance ★★ ⚠ same condition
TYROBP p.Val42Met 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/tyrobp-p-ser20ile (accessed [today's date]).

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