Is RHBDF2 p.Arg235Gln (c.704G>A) pathogenic?

RHBDF2 p.Arg235Gln (c.704G>A) is classified Conflicting classifications of pathogenicity in RHBDF2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.069); Rare (popmax 0.132%, afr); Associated with Inborn genetic diseases.

What condition is associated with RHBDF2 p.Arg235Gln (c.704G>A)?

RHBDF2 p.Arg235Gln (c.704G>A) is associated with Inborn genetic diseases, palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Arg235Gln (c.704G>A) in the general population?

RHBDF2 p.Arg235Gln (c.704G>A) is rare (popmax 0.132%, afr) (gnomAD).

What do computational predictors say about RHBDF2 p.Arg235Gln (c.704G>A)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

RHBDF2 p.Arg235Gln

c.704G>A · rs145136848 · VCV325449

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -7.85	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 -0.24	GERP -4.2, phastCons 0.003
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	14.47	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 R264Q vs ClinVar R235Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% African / African-American · 99/75,058 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.00744% 120/1,613,192 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.132%	758
East Asian	0.0156%	6,413
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.0022%	45,544
European (non-Finnish)	0.000424%	235,998

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.Arg235Gln
Coding: c.704G>A
MANE Select: NM_001005498
dbSNP: rs145136848
Type: single nucleotide variant
Location: chr17:76477754 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 264 UniProt numbering: the 'involved in interaction with frmd8' 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

Also linked: palmoplantar keratoderma-esophageal carcinoma syndrome

Similar variants

RHBDF2 p.Arg235Trp Uncertain significance ★★ ⚠ same residue
RHBDF2 p.Arg235= Likely benign ★ same residue
RHBDF2 p.Ile157Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
RHBDF2 c.151-27G>T Uncertain significance ★★ ⚠ same condition
RHBDF2 c.151-86G>A Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Ala397Ser Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Ala700Thr Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Ala725Val 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-arg235gln (accessed [today's date]).

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