Is RHOBTB2 p.Arg461Pro (c.1382G>C) pathogenic?

RHOBTB2 p.Arg461Pro (c.1382G>C) is classified Conflicting classifications of pathogenicity in RHOBTB2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-07). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 64.

What condition is associated with RHOBTB2 p.Arg461Pro (c.1382G>C)?

RHOBTB2 p.Arg461Pro (c.1382G>C) is associated with developmental and epileptic encephalopathy, 64 (ClinVar).

How common is RHOBTB2 p.Arg461Pro (c.1382G>C) in the general population?

RHOBTB2 p.Arg461Pro (c.1382G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RHOBTB2 p.Arg461Pro (c.1382G>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

RHOBTB2 p.Arg461Pro

c.1382G>C · rs1554504663 · VCV1515448

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 64

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic · top 9% in RHOBTB2
REVEL	0.507	indeterminate
SaProt	LLR -9.73	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 10 kb · p 8.8e-07 · regional, not allelic
Overall
CADD	33.0	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

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: RHOBTB2
Protein: p.Arg461Pro
Coding: c.1382G>C
MANE Select: NM_015178
dbSNP: rs1554504663
Type: single nucleotide variant
Location: chr8:23007627 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 461: a UniProt-annotated variant site (found in autosomal recessive neurodevelopmental disorder; likely pathogenic); a UniProt-annotated variant site (found in autosomal recessive neurodevelopmental disorder; uncertain significance); a UniProt-annotated variant site (in dee64; pathogenic; reduced rhobtb2 proteasomal degradation; does not affect interaction with cul3; no effect on interaction with msi2)

Full RHOBTB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 64 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RHOBTB2 p.Arg461His Pathogenic/Likely pathogenic ★★ ⚠ same residue
RHOBTB2 p.Arg461Cys Uncertain significance ★ ⚠ same residue
RHOBTB2 p.Arg485Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RHOBTB2 p.Arg489Gln Pathogenic ★★ ⚠ same condition
RHOBTB2 p.Arg489Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
RHOBTB2 p.Arg489Trp Pathogenic/Likely pathogenic ★★ same condition
RHOBTB2 p.Arg94Cys Pathogenic/Likely pathogenic ★★ same condition
RHOBTB2 p.Asn488Asp Pathogenic/Likely pathogenic ★★ ⚠ 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/rhobtb2-p-arg461pro (accessed [today's date]).

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