Is TYRO3 p.Arg478Trp (c.1432C>T) pathogenic?

TYRO3 p.Arg478Trp (c.1432C>T) is classified Uncertain significance in TYRO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.4659); Ultra-rare (popmax 0.0824%, eas).

How common is TYRO3 p.Arg478Trp (c.1432C>T) in the general population?

TYRO3 p.Arg478Trp (c.1432C>T) is ultra-rare (popmax 0.0824%, eas) (gnomAD).

What do computational predictors say about TYRO3 p.Arg478Trp (c.1432C>T)?

AlphaMissense predicts ambiguous (score 0.4659) — an in-silico prediction, not a clinical call.

TYRO3 p.Arg478Trp

c.1432C>T · VCV4194491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0824%, eas)

Computational evidence

Protein change
AlphaMissense	0.4659	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -9.22	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 19 kb · p 8.2e-20 · regional, not allelic
Overall
CADD	27.2	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 0.0824% East Asian · 37/44,882 alleles

Filtering AF 0.0615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00576% 93/1,614,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0824%	1,213
European (non-Finnish)	0.00449%	22,265
Admixed American	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,506
Finnishnot grpmax-eligible	0.00156%	64,012

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.Arg478Trp
Coding: c.1432C>T
MANE Select: NM_006293
Type: single nucleotide variant
Location: chr15:41570289 (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.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-arg478trp (accessed [today's date]).

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