Is RHBDF2 p.Ala636= (c.1908T>C) pathogenic?

RHBDF2 p.Ala636= (c.1908T>C) is classified Benign in RHBDF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-30). Rare (popmax 0.102%, eas); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Ala636= (c.1908T>C)?

RHBDF2 p.Ala636= (c.1908T>C) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Ala636= (c.1908T>C) in the general population?

RHBDF2 p.Ala636= (c.1908T>C) is rare (popmax 0.102%, eas) (gnomAD).

RHBDF2 p.Ala636=

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

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

c.1908T>C · rs529460959 · VCV888696

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.102%, 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	<0.2	all four deltas below 0.2 · A>T here scores Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.3	GERP -3.9
Overall
CADD	0.042	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.102% East Asian · 46/44,880 alleles

Filtering AF 0.0789% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0706%

Overall 0.00316% 51/1,613,326 alleles · rare exomes 39/1,461,028 · genomes 12/152,298 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.102%	976
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00017%	589,633

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.Ala636=
Coding: c.1908T>C
MANE Select: NM_001005498
dbSNP: rs529460959
Type: single nucleotide variant
Location: chr17:76473007 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 636: 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-ala636 (accessed [today's date]).

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