Is TYRO3 p.Arg459Pro (c.1376G>C) pathogenic?

TYRO3 p.Arg459Pro (c.1376G>C) is classified Uncertain significance in TYRO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.7108); Absent from gnomAD v4.1.

How common is TYRO3 p.Arg459Pro (c.1376G>C) in the general population?

TYRO3 p.Arg459Pro (c.1376G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TYRO3 p.Arg459Pro (c.1376G>C)?

AlphaMissense predicts likely pathogenic (score 0.7108) — an in-silico prediction, not a clinical call.

TYRO3 p.Arg459Pro

c.1376G>C · VCV4194497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7108 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7108	likely pathogenic
REVEL	0.331	indeterminate
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 19 kb · p 8.2e-20 · regional, not allelic
Overall
CADD	25.6	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

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: TYRO3
Protein: p.Arg459Pro
Coding: c.1376G>C
MANE Select: NM_006293
Type: single nucleotide variant
Location: chr15:41570150 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 1 PDB

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

Similar variants

TYRO3 p.Arg459Gln Uncertain significance ★ ⚠ same residue
TYRO3 p.Arg459Trp Uncertain significance ★ ⚠ same residue
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

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-arg459pro (accessed [today's date]).

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