Is RHBDF2 p.Arg90His (c.269G>A) pathogenic?

RHBDF2 p.Arg90His (c.269G>A) is classified Uncertain significance in RHBDF2 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.2308); Very rare (popmax 0.00223%, eas); Associated with hepatoblastoma.

What condition is associated with RHBDF2 p.Arg90His (c.269G>A)?

RHBDF2 p.Arg90His (c.269G>A) is associated with hepatoblastoma (ClinVar).

How common is RHBDF2 p.Arg90His (c.269G>A) in the general population?

RHBDF2 p.Arg90His (c.269G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Hepatoblastoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RHBDF2 p.Arg90His (c.269G>A)?

AlphaMissense predicts likely benign (score 0.2308) — an in-silico prediction, not a clinical call.

RHBDF2 p.Arg90His

c.269G>A · rs368409953 · VCV1343298

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2308 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hepatoblastoma

Computational evidence

Protein change
AlphaMissense	0.2308	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -8.53	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 7.5	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	33.0	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 R119H vs ClinVar R90H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,826 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000747% 12/1,607,018 alleles · very rare exomes 12/1,454,948 · genomes 0/152,070 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,826
European (non-Finnish)	0.000933%	107,179

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.Arg90His
Coding: c.269G>A
MANE Select: NM_001005498
dbSNP: rs368409953
Type: single nucleotide variant
Location: chr17:76479736 (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

hepatoblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hepatoblastoma (Orphanet):

Inheritance: Not applicable
Onset: Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

RHBDF2 p.Arg90Cys Uncertain significance ★ ⚠ same residue
RHBDF2 p.Ile157Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
RHBDF2 c.151-27G>T Uncertain significance ★★ ⚠ same type
RHBDF2 c.151-86G>A Uncertain significance ★★ ⚠ same type
RHBDF2 p.Ala397Ser Uncertain significance ★★ ⚠ same type
RHBDF2 p.Ala700Thr Uncertain significance ★★ ⚠ same type
RHBDF2 p.Ala725Val Uncertain significance ★★ ⚠ same type
RHBDF2 p.Arg113His 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/rhbdf2-p-arg90his (accessed [today's date]).

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