Is RHOBTB2 p.Pro404Ser (c.1210C>T) pathogenic?

RHOBTB2 p.Pro404Ser (c.1210C>T) is classified Uncertain significance in RHOBTB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.6932); Very rare (popmax 0.0011%, sas).

How common is RHOBTB2 p.Pro404Ser (c.1210C>T) in the general population?

RHOBTB2 p.Pro404Ser (c.1210C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RHOBTB2 p.Pro404Ser (c.1210C>T)?

AlphaMissense predicts likely pathogenic (score 0.6932) — an in-silico prediction, not a clinical call.

RHOBTB2 p.Pro404Ser

c.1210C>T · VCV4812169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6932	likely pathogenic
REVEL	0.219	benign-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 10 kb · p 8.8e-07 · regional, not allelic
Overall
CADD	26.2	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 0.0011% South Asian · 1/91,078 alleles

Overall 6.2e-05% 1/1,614,174 alleles · very rare exomes 1/1,461,878 · genomes 0/152,296 · 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: RHOBTB2
Protein: p.Pro404Ser
Coding: c.1210C>T
MANE Select: NM_015178
Type: single nucleotide variant
Location: chr8:23007455 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 404: the btb 1 domain; 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)

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

Similar variants

RHOBTB2 p.Pro404= Likely benign ★ same residue
RHOBTB2 p.Arg461His Pathogenic/Likely pathogenic ★★ ⚠ same type
RHOBTB2 p.Arg485Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
RHOBTB2 p.Arg489Gln Pathogenic ★★ ⚠ same type
RHOBTB2 p.Arg489Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
RHOBTB2 p.Arg489Trp Pathogenic/Likely pathogenic ★★ same type
RHOBTB2 p.Arg94Cys Pathogenic/Likely pathogenic ★★ same type
RHOBTB2 p.Asn488Asp Pathogenic/Likely pathogenic ★★ ⚠ 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/rhobtb2-p-pro404ser (accessed [today's date]).

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