Is RHBDF2 p.Pro282Gln (c.845C>A) pathogenic?

RHBDF2 p.Pro282Gln (c.845C>A) is classified Uncertain significance in RHBDF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.5149); Very rare (popmax 0.00442%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RHBDF2 p.Pro282Gln (c.845C>A)?

RHBDF2 p.Pro282Gln (c.845C>A) is associated with Inborn genetic diseases (ClinVar).

How common is RHBDF2 p.Pro282Gln (c.845C>A) in the general population?

RHBDF2 p.Pro282Gln (c.845C>A) is very rare (popmax 0.00442%, nfe) (gnomAD).

What do computational predictors say about RHBDF2 p.Pro282Gln (c.845C>A)?

AlphaMissense predicts ambiguous (score 0.5149) — an in-silico prediction, not a clinical call.

RHBDF2 p.Pro282Gln

c.845C>A · rs750059653 · VCV2588340

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5149	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -7.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P311Q vs ClinVar P282Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00442% European (non-Finnish) · 52/1,177,280 alleles

Filtering AF 0.00343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00311%

Overall 0.00349% 56/1,606,590 alleles · very rare exomes 55/1,454,450 · genomes 1/152,140 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00482%	20,729
European (non-Finnish)grpmax	0.00442%	22,640
East Asian	0.00223%	44,852

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: RHBDF2
Protein: p.Pro282Gln
Coding: c.845C>A
MANE Select: NM_001005498
dbSNP: rs750059653
Type: single nucleotide variant
Location: chr17:76477255 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB

Full RHBDF2 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

RHBDF2 p.Ala700Thr Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg205His Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg206Cys Uncertain significance ★★ same condition
RHBDF2 p.Arg226Cys Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg235Trp Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg351Cys Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg663Cys 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/rhbdf2-p-pro282gln (accessed [today's date]).

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