Is RHBDF2 p.Ser263Phe (c.788C>T) pathogenic?

RHBDF2 p.Ser263Phe (c.788C>T) is classified Benign in RHBDF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: ambiguous (0.3926); Common (popmax 6.19%, amr) — too common for a highly-penetrant pathogenic allele; Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Ser263Phe (c.788C>T)?

RHBDF2 p.Ser263Phe (c.788C>T) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

What do computational predictors say about RHBDF2 p.Ser263Phe (c.788C>T)?

AlphaMissense predicts ambiguous (score 0.3926) — an in-silico prediction, not a clinical call.

RHBDF2 p.Ser263Phe

Q: How common is RHBDF2 p.Ser263Phe (c.788C>T) in the general population?

RHBDF2 p.Ser263Phe (c.788C>T) is common (popmax 6.19%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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

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

c.788C>T · rs116968311 · VCV325448

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3926 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.19%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

palmoplantar keratoderma-esophageal carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.3926	ambiguous
REVEL	0.339	indeterminate
SaProt	LLR -8.25	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	25.5	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 S292F vs ClinVar S263F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.19% Admixed American · 3,716/59,998 alleles

Filtering AF 6.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.96%

Overall 0.246% 3,972/1,613,984 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	6.19%	16
Remaining individualsnot grpmax-eligible	0.181%	553
East Asian	0.111%	897
South Asian	0.0395%	2,530
African / African-American	0.0293%	3,411
European (non-Finnish)	0.00297%	33,714

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.Ser263Phe
Coding: c.788C>T
MANE Select: NM_001005498
dbSNP: rs116968311
Type: single nucleotide variant
Location: chr17:76477670 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB

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-ser263phe (accessed [today's date]).

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