Is RHBDF2 p.Arg412Trp (c.1234C>T) pathogenic?

RHBDF2 p.Arg412Trp (c.1234C>T) is classified Uncertain significance in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-27). AlphaMissense: ambiguous (0.347); Very rare (popmax 0.0011%, sas); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

What condition is associated with RHBDF2 p.Arg412Trp (c.1234C>T)?

RHBDF2 p.Arg412Trp (c.1234C>T) is associated with palmoplantar keratoderma-esophageal carcinoma syndrome (ClinVar).

How common is RHBDF2 p.Arg412Trp (c.1234C>T) in the general population?

RHBDF2 p.Arg412Trp (c.1234C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RHBDF2 p.Arg412Trp (c.1234C>T)?

AlphaMissense predicts ambiguous (score 0.347) — an in-silico prediction, not a clinical call.

RHBDF2 p.Arg412Trp

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

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

c.1234C>T · rs1315536442 · VCV2678344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

palmoplantar keratoderma-esophageal carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.347	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -5.69	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.89	GERP -1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,466 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	23.9	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 R441W vs ClinVar R412W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,072 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,802 alleles · very rare exomes 7/1,461,620 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,474
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000509%	196,640

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg412Trp
Coding: c.1234C>T
MANE Select: NM_001005498
dbSNP: rs1315536442
Type: single nucleotide variant
Location: chr17:76474798 (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.Arg412Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg412trp (accessed [today's date]).

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