Is RHBDF2 p.Arg80His (c.239G>A) pathogenic?

RHBDF2 p.Arg80His (c.239G>A) is classified Benign/Likely benign in RHBDF2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-23). AlphaMissense: likely benign (0.0777); Rare (popmax 0.193%, mid); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Arg80His (c.239G>A)?

RHBDF2 p.Arg80His (c.239G>A) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Arg80His (c.239G>A) in the general population?

RHBDF2 p.Arg80His (c.239G>A) is rare (popmax 0.193%, mid) (gnomAD).

What do computational predictors say about RHBDF2 p.Arg80His (c.239G>A)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

RHBDF2 p.Arg80His

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

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

c.239G>A · rs143449348 · VCV325464

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.193%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

palmoplantar keratoderma-esophageal carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.62	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 1.1	GERP 0.98, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	21.6	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 R109H vs ClinVar R80H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.193% Middle Eastern · 11/5,698 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0837%

Overall 0.0151% 243/1,612,140 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.193%	518
Ashkenazi Jewishnot grpmax-eligible	0.179%	558
Remaining individualsnot grpmax-eligible	0.0593%	1,687
African / African-American	0.0401%	2,494
South Asian	0.0253%	3,956
Admixed American	0.02%	4,995
East Asian	0.00669%	14,942
European (non-Finnish)	0.00627%	15,944

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.Arg80His
Coding: c.239G>A
MANE Select: NM_001005498
dbSNP: rs143449348
Type: single nucleotide variant
Location: chr17:76479766 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 80: the 'disordered' 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.Arg80Cys Benign/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.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-arg80his (accessed [today's date]).

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