Is RHBDF2 p.Arg235Trp (c.703C>T) pathogenic?

RHBDF2 p.Arg235Trp (c.703C>T) is classified Uncertain significance in RHBDF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-21). AlphaMissense: likely benign (0.1035); Ultra-rare (popmax 0.0401%, eas); Associated with Inborn genetic diseases.

What condition is associated with RHBDF2 p.Arg235Trp (c.703C>T)?

RHBDF2 p.Arg235Trp (c.703C>T) is associated with Inborn genetic diseases, palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Arg235Trp (c.703C>T) in the general population?

RHBDF2 p.Arg235Trp (c.703C>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about RHBDF2 p.Arg235Trp (c.703C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

RHBDF2 p.Arg235Trp

c.703C>T · rs541445182 · VCV3153998

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.92, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R264W vs ClinVar R235W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0401% East Asian · 18/44,884 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00415% 67/1,612,982 alleles · ultra-rare exomes 55/1,460,636 · genomes 12/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,494
African / African-American	0.0107%	9,383
Admixed American	0.00833%	12,003
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.0028%	35,757

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.Arg235Trp
Coding: c.703C>T
MANE Select: NM_001005498
dbSNP: rs541445182
Type: single nucleotide variant
Location: chr17:76477755 (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.Arg235Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg235trp (accessed [today's date]).

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