Is TUSC3 p.Arg63Pro (c.188G>C) pathogenic?

TUSC3 p.Arg63Pro (c.188G>C) is classified Uncertain significance in TUSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-31). AlphaMissense: likely pathogenic (0.9722); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TUSC3 p.Arg63Pro (c.188G>C)?

TUSC3 p.Arg63Pro (c.188G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TUSC3 p.Arg63Pro (c.188G>C) in the general population?

TUSC3 p.Arg63Pro (c.188G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TUSC3 p.Arg63Pro (c.188G>C)?

AlphaMissense predicts likely pathogenic (score 0.9722) — an in-silico prediction, not a clinical call.

TUSC3 p.Arg63Pro

c.188G>C · rs1805325913 · VCV1782049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9722 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9722	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -16.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 217 kb · p 0.00011 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: TUSC3
Protein: p.Arg63Pro
Coding: c.188G>C
MANE Select: NM_006765
dbSNP: rs1805325913
Type: single nucleotide variant
Location: chr8:15623129 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.78 · 4 PDB
Residue 63: the thioredoxin domain

Full TUSC3 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

TUSC3 p.Arg63Gly Uncertain significance ★ ⚠ same residue
TUSC3 p.Arg63= Uncertain significance ★ same residue
TUSC3 p.Arg63Cys Uncertain significance ★ ⚠ same residue
TUSC3 p.Gln177Ter Pathogenic ★★ same condition
TUSC3 p.Arg159Lys Uncertain significance ★★ ⚠ same condition
TUSC3 p.Arg15Gln Uncertain significance ★★ ⚠ same condition
TUSC3 p.Arg15Pro Uncertain significance ★★ ⚠ same condition
TUSC3 p.Arg312Trp 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/tusc3-p-arg63pro (accessed [today's date]).

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