Is RHBDF2 p.Phe696= (c.2088C>T) pathogenic?

RHBDF2 p.Phe696= (c.2088C>T) is classified Uncertain significance in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0169%, mid); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Phe696= (c.2088C>T)?

RHBDF2 p.Phe696= (c.2088C>T) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Phe696= (c.2088C>T) in the general population?

RHBDF2 p.Phe696= (c.2088C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

RHBDF2 p.Phe696=

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

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

c.2088C>T · rs202160090 · VCV888693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

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 -3.6	GERP -3.6
Overall
CADD	4.663	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,922 alleles

Filtering AF 0.00369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00239%

Overall 0.0014% 22/1,569,466 alleles · ultra-rare exomes 16/1,417,108 · genomes 6/152,358 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,922
Admixed American	0.00939%	10,647
African / African-American	0.00673%	14,861
South Asian	0.00466%	21,442
Remaining individualsnot grpmax-eligible	0.00164%	60,828
European (non-Finnish)	0.000518%	192,899

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.Phe696=
Coding: c.2088C>T
MANE Select: NM_001005498
dbSNP: rs202160090
Type: single nucleotide variant
Location: chr17:76472029 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 696: an α-helix

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-phe696 (accessed [today's date]).

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