Is RHBDF2 p.Ser10Arg (c.28A>C) pathogenic?

RHBDF2 p.Ser10Arg (c.28A>C) is classified Benign in RHBDF2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1893); Common (popmax 9.05%, eas) — too common for a highly-penetrant pathogenic allele; Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Ser10Arg (c.28A>C)?

RHBDF2 p.Ser10Arg (c.28A>C) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

What do computational predictors say about RHBDF2 p.Ser10Arg (c.28A>C)?

AlphaMissense predicts likely benign (score 0.1893) — an in-silico prediction, not a clinical call.

RHBDF2 p.Ser10Arg

Q: How common is RHBDF2 p.Ser10Arg (c.28A>C) in the general population?

RHBDF2 p.Ser10Arg (c.28A>C) is common (popmax 9.05%, eas) — 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.28A>C · rs80133178 · VCV325468

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1893 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.05%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

palmoplantar keratoderma-esophageal carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.1893	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP 0.83, phastCons 0.004
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	19.27	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.05% East Asian · 4,037/44,584 alleles

Filtering AF 8.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.73%

Overall 0.41% 6,562/1,601,978 alleles · common exomes 5,825/1,450,100 · genomes 737/151,878 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	9.05%	11
Admixed American	1.96%	51
Remaining individualsnot grpmax-eligible	0.392%	255
Ashkenazi Jewishnot grpmax-eligible	0.327%	306
South Asian	0.188%	531
Middle Eastern	0.0858%	1,165
European (non-Finnish)	0.0676%	1,479
African / African-American	0.0508%	1,969
Finnishnot grpmax-eligible	0.034%	2,945

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.Ser10Arg
Coding: c.28A>C
MANE Select: NM_001005498
dbSNP: rs80133178
Type: single nucleotide variant
Location: chr17:76481497 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB
Residue 10: 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.Ser10Asn Uncertain significance ★★ ⚠ same residue
RHBDF2 p.Ser10Ile Uncertain significance ★ ⚠ 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

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-ser10arg (accessed [today's date]).

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