Is RHBDF2 p.Pro182= (c.546G>A) pathogenic?

RHBDF2 p.Pro182= (c.546G>A) is classified Benign/Likely benign in RHBDF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-23). Low-frequency (popmax 1.03%, eas); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Pro182= (c.546G>A)?

RHBDF2 p.Pro182= (c.546G>A) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Pro182= (c.546G>A) in the general population?

RHBDF2 p.Pro182= (c.546G>A) is low-frequency (popmax 1.03%, eas) (gnomAD).

RHBDF2 p.Pro182=

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

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

c.546G>A · rs3744044 · VCV325454

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.03%, eas)

Conditions

palmoplantar keratoderma-esophageal carcinoma syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.9
Overall
CADD	0.403	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.03% East Asian · 463/44,802 alleles

Filtering AF 0.956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.925%

Overall 0.0463% 742/1,603,950 alleles · low-frequency exomes 607/1,451,772 · genomes 135/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.03%	97
African / African-American	0.183%	547
South Asian	0.0616%	1,623
Remaining individualsnot grpmax-eligible	0.0306%	3,267
Admixed American	0.0186%	5,387
Middle Eastern	0.0167%	6,002
Finnishnot grpmax-eligible	0.00789%	12,672
European (non-Finnish)	0.00434%	23,033

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.Pro182=
Coding: c.546G>A
MANE Select: NM_001005498
dbSNP: rs3744044
Type: single nucleotide variant
Location: chr17:76478932 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 182: 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.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
RHBDF2 p.Arg237Trp 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-pro182 (accessed [today's date]).

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