Is RHBDF2 p.Ala83Asp (c.248C>A) pathogenic?

RHBDF2 p.Ala83Asp (c.248C>A) is classified Uncertain significance in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-26). AlphaMissense: likely benign (0.2634); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with RHBDF2 p.Ala83Asp (c.248C>A)?

RHBDF2 p.Ala83Asp (c.248C>A) is associated with Inborn genetic diseases (ClinVar).

How common is RHBDF2 p.Ala83Asp (c.248C>A) in the general population?

RHBDF2 p.Ala83Asp (c.248C>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about RHBDF2 p.Ala83Asp (c.248C>A)?

AlphaMissense predicts likely benign (score 0.2634) — an in-silico prediction, not a clinical call.

RHBDF2 p.Ala83Asp

c.248C>A · rs536930030 · VCV3153994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2634 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2634	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A112D vs ClinVar A83D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,968 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,611,514 alleles · very rare exomes 1/1,459,428 · genomes 1/152,086 · 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: RHBDF2
Protein: p.Ala83Asp
Coding: c.248C>A
MANE Select: NM_001005498
dbSNP: rs536930030
Type: single nucleotide variant
Location: chr17:76479757 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 112 UniProt numbering: the 'disordered' region

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-ala83asp (accessed [today's date]).

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