Is RUSC2 p.Trp1484Arg (c.4450T>C) pathogenic?

RUSC2 p.Trp1484Arg (c.4450T>C) is classified Uncertain significance in RUSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.9319); Very rare (popmax 0.00305%, nfe).

How common is RUSC2 p.Trp1484Arg (c.4450T>C) in the general population?

RUSC2 p.Trp1484Arg (c.4450T>C) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about RUSC2 p.Trp1484Arg (c.4450T>C)?

AlphaMissense predicts likely pathogenic (score 0.9319) — an in-silico prediction, not a clinical call.

RUSC2 p.Trp1484Arg

c.4450T>C · rs762700848 · VCV1676551

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9319	likely pathogenic · top 6% in RUSC2
REVEL	0.531	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	27.0	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 0.00305% European (non-Finnish) · 36/1,180,000 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00223% 36/1,613,984 alleles · very rare exomes 31/1,461,774 · genomes 5/152,210 · joint denominator

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: RUSC2
Protein: p.Trp1484Arg
Coding: c.4450T>C
MANE Select: NM_014806
dbSNP: rs762700848
Type: single nucleotide variant
Location: chr9:35561281 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 45.82 · 1 PDB
Residue 1484: the sh3 domain; a UniProt-annotated variant site (in mrt61; uncertain significance)

Full RUSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RUSC2 p.Arg1393Ter Pathogenic/Likely pathogenic ★★ same type
RUSC2 p.Ala1054Thr Uncertain significance ★★ ⚠ same type
RUSC2 p.Ala1268Thr Uncertain significance ★★ ⚠ same type
RUSC2 p.Ala126Thr Uncertain significance ★★ ⚠ same type
RUSC2 p.Ala319Thr Uncertain significance ★★ ⚠ same type
RUSC2 p.Ala585Thr Uncertain significance ★★ ⚠ same type
RUSC2 p.Ala745Thr Uncertain significance ★★ ⚠ same type
RUSC2 p.Ala886Asp 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/rusc2-p-trp1484arg (accessed [today's date]).

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