Is RHBDF2 p.Gly343= (c.1029C>T) pathogenic?

RHBDF2 p.Gly343= (c.1029C>T) is classified Benign in RHBDF2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). Common (popmax 12%, sas) — too common for a highly-penetrant pathogenic allele; Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Gly343= (c.1029C>T)?

RHBDF2 p.Gly343= (c.1029C>T) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

RHBDF2 p.Gly343=

Q: How common is RHBDF2 p.Gly343= (c.1029C>T) in the general population?

RHBDF2 p.Gly343= (c.1029C>T) is common (popmax 12%, sas) — 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.1029C>T · rs61742551 · VCV325443

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 12%, sas) — too common for a highly-penetrant pathogenic allele

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 -2.1	GERP -3.2
Overall
CADD	9.947	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12% South Asian · 10,951/91,082 alleles

Filtering AF 11.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.8%

Overall 3.09% 49,935/1,613,682 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	12%	8
African / African-American	11.2%	9
East Asian	9.24%	11
Admixed American	7.09%	14
Ashkenazi Jewishnot grpmax-eligible	4.28%	23
Middle Eastern	3.75%	27
Remaining individualsnot grpmax-eligible	3.51%	28
European (non-Finnish)	1.54%	65
Finnishnot grpmax-eligible	0.464%	216

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.Gly343=
Coding: c.1029C>T
MANE Select: NM_001005498
dbSNP: rs61742551
Type: single nucleotide variant
Location: chr17:76476916 (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.Gly343Ser 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
RHBDF2 p.Arg235Trp 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-gly343 (accessed [today's date]).

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