Is TYROBP p.Pro40Leu (c.119C>T) pathogenic?

TYROBP p.Pro40Leu (c.119C>T) is classified Uncertain significance in TYROBP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.4051); Rare (popmax 0.396%, mid); Associated with Inborn genetic diseases.

What condition is associated with TYROBP p.Pro40Leu (c.119C>T)?

TYROBP p.Pro40Leu (c.119C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TYROBP p.Pro40Leu (c.119C>T) in the general population?

TYROBP p.Pro40Leu (c.119C>T) is rare (popmax 0.396%, mid) (gnomAD).

What do computational predictors say about TYROBP p.Pro40Leu (c.119C>T)?

AlphaMissense predicts ambiguous (score 0.4051) — an in-silico prediction, not a clinical call.

TYROBP p.Pro40Leu

c.119C>T · rs201680032 · VCV595538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4051 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.396%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4051	ambiguous
REVEL	0.603	indeterminate
SaProt	LLR -9.39	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP -0.45, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 3,656 bp · p 0.43 · regional, not allelic
Overall
CADD	24.1	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 0.396% Middle Eastern · 24/6,062 alleles

Filtering AF 0.273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.00465% 75/1,613,886 alleles · rare exomes 72/1,461,662 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.396%	253
Remaining individualsnot grpmax-eligible	0.0064%	15,625
South Asian	0.00439%	22,769
European (non-Finnish)	0.00348%	28,777
East Asian	0.00223%	44,882
Admixed American	0.00167%	60,004

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: TYROBP
Protein: p.Pro40Leu
Coding: c.119C>T
MANE Select: NM_003332
dbSNP: rs201680032
Type: single nucleotide variant
Location: chr19:35907556 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.10 · 5 PDB
Residue 40: an α-helix

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.Pro40= Likely benign ★ 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.Ser99Leu Uncertain significance ★★ ⚠ same condition
TYROBP p.Val38Met Uncertain significance ★★ ⚠ same condition
TYROBP p.Val42Met Uncertain significance ★★ ⚠ same condition
TYROBP p.Val68Leu 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-pro40leu (accessed [today's date]).

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