Is TYRO3 p.Pro755Leu (c.2264C>T) pathogenic?

TYRO3 p.Pro755Leu (c.2264C>T) is classified Uncertain significance in TYRO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0164%, mid).

How common is TYRO3 p.Pro755Leu (c.2264C>T) in the general population?

TYRO3 p.Pro755Leu (c.2264C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TYRO3 p.Pro755Leu (c.2264C>T)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

TYRO3 p.Pro755Leu

c.2264C>T · rs372061850 · VCV2375535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -9.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -1.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 19 kb · p 8.2e-20 · regional, not allelic
Overall
CADD	23.8	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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00973% 157/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.0134%	7,484
European (non-Finnish)	0.0114%	8,806
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.00667%	15,003
African / African-American	0.004%	24,986
South Asian	0.0022%	45,546

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: TYRO3
Protein: p.Pro755Leu
Coding: c.2264C>T
MANE Select: NM_006293
dbSNP: rs372061850
Type: single nucleotide variant
Location: chr15:41573797 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 1 PDB
Residue 755: the protein kinase domain

Full TYRO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TYRO3 p.Ser543Phe Uncertain significance ★★ ⚠ same type
TYRO3 p.Ala815= Benign ★★ same type
TYRO3 p.Ala815Val Benign ★★ ⚠ same type
TYRO3 p.Gly675Arg Benign ★★ same type
TYRO3 p.Pro183= Benign ★★ same type
TYRO3 p.Thr458= Benign ★★ same type
TYRO3 p.Val669Leu Benign ★★ same type
TYRO3 p.Ala149Ser Uncertain significance ★ ⚠ same type

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/tyro3-p-pro755leu (accessed [today's date]).

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