Is RHBDF2 p.Arg237Trp (c.709C>T) pathogenic?

RHBDF2 p.Arg237Trp (c.709C>T) is classified Uncertain significance in RHBDF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-22). AlphaMissense: likely benign (0.0887); Very rare (popmax 0.005%, amr); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Arg237Trp (c.709C>T)?

RHBDF2 p.Arg237Trp (c.709C>T) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Arg237Trp (c.709C>T) in the general population?

RHBDF2 p.Arg237Trp (c.709C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about RHBDF2 p.Arg237Trp (c.709C>T)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

RHBDF2 p.Arg237Trp

Q: How is Palmoplantar keratoderma-esophageal carcinoma syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.709C>T · rs763172645 · VCV2678348

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

palmoplantar keratoderma-esophageal carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.45, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	24.0	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 R266W vs ClinVar R237W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00366% 59/1,613,214 alleles · very rare exomes 55/1,461,022 · genomes 4/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
East Asian	0.00445%	22,448
European (non-Finnish)	0.00432%	23,137
Remaining individualsnot grpmax-eligible	0.0032%	31,241
South Asian	0.0011%	91,088

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.Arg237Trp
Coding: c.709C>T
MANE Select: NM_001005498
dbSNP: rs763172645
Type: single nucleotide variant
Location: chr17:76477749 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 266 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

palmoplantar keratoderma-esophageal carcinoma syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Palmoplantar keratoderma-esophageal carcinoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

RHBDF2 p.Arg237Gln Uncertain significance ★ ⚠ 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.Ala725Val Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg113His Uncertain significance ★★ ⚠ same condition
RHBDF2 p.Arg235Trp 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-arg237trp (accessed [today's date]).

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