# NM_001005498.4(RHBDF2):c.1812G>A (p.Val604=)

https://sugi.bio/variant/rhbdf2-p-val604

## Summary

**RHBDF2 p.Val604= (c.1812G>A)** is classified **Benign/Likely benign** in RHBDF2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-03-01). Rare (popmax 0.72%, nfe); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs138683747 · 7 submitters · 1 linked condition · rare (popmax 0.72%, nfe)

## For patients & families {#patients}

This is a change in the RHBDF2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to palmoplantar keratoderma-esophageal carcinoma syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult |
| Diagnostic panels | RHBDF2 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Palmoplantar keratoderma-esophageal carcinoma syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Palmoplantar keratoderma — Very frequent (99-80%)
- Nausea and vomiting — Very frequent (99-80%)
- Gastrointestinal hemorrhage — Very frequent (99-80%)
- Abnormal large intestine morphology — Very frequent (99-80%)
- Esophageal neoplasm — Very frequent (99-80%)
- Ascites — Frequent (79-30%)
- Weight loss — Frequent (79-30%)
- Dysphagia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003102/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RHBDF2](https://sugi.bio/atlas/gene/RHBDF2/) |
| Protein change (HGVS p.) | p.Val604= |
| Coding change (HGVS c.) | c.1812G>A |
| MANE Select transcript | [NM_001005498](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005498) |
| dbSNP | [rs138683747](https://www.ncbi.nlm.nih.gov/snp/rs138683747/) |
| Variant type | single nucleotide variant |
| Location | chr17:76473103-76473103 (GRCh38) |
| ClinVar | [VCV325427](https://www.ncbi.nlm.nih.gov/clinvar/variation/325427/) |

**All HGVS expressions:** `LRG_532:g.33325G>A`, `LRG_532t1:c.1899G>A`, `NC_000017.10:g.74469185C>T`, `NC_000017.11:g.76473103C>T`, `NG_032852.1:g.33325G>A`, `NM_001005498.4:c.1812G>A`, `NM_001376228.1:c.1812G>A`, `NM_001376229.1:c.1812G>A`, `NM_001376230.1:c.1812G>A`, `NM_024599.5:c.1899G>A`, `NR_164785.1:n.2531G>A`, `NR_164786.1:n.2273G>A`, `NR_164787.1:n.2589G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.292, GERP -0.499, phastCons 0.18 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.854**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.72%** (nfe) · FAF95 0.707% · FAF99 0.701% · 8,486/1,179,242 in the highest group · 9,376/1,613,240 alleles overall — rare (popmax 0.72%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.72% | 139 |
| Finnish (not grpmax-eligible) | 0.489% | 204 |
| Remaining individuals (not grpmax-eligible) | 0.437% | 229 |
| Admixed American | 0.293% | 341 |
| Middle Eastern | 0.149% | 673 |
| Amish (not grpmax-eligible) | 0.11% | 912 |
| African / African-American | 0.0933% | 1,072 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0406% | 2,466 |
| South Asian | 0.0395% | 2,530 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RHBDF2** population constraint: LOEUF 0.545, pLI 0.15213, missense-Z 2.7942; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **palmoplantar keratoderma-esophageal carcinoma syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **604** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 67.53, 28% of residues very-high.

**5 experimental structure(s)** (PDB): [8SNL](https://www.rcsb.org/structure/8SNL), [8SNM](https://www.rcsb.org/structure/8SNM), [8SNN](https://www.rcsb.org/structure/8SNN), [8SNO](https://www.rcsb.org/structure/8SNO), [9O58](https://www.rcsb.org/structure/9O58).

## What this gene does {#gene-function}

*Describes the biological roles of RHBDF2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** RHBDF2 participates in disease-associated pathways. In Reactome, RHBDF2 is annotated in disease pathway(s) including **CD163 mediating an anti-inflammatory response**.

**Disease mechanism (Reactome):** RHBDF2 loss or alteration is curated in [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834).

### Pathways affected {#pathways}

RHBDF2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834) | curated |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (4 Likely benign, 3 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |

## Associated conditions {#conditions}

[palmoplantar keratoderma-esophageal carcinoma syndrome](https://sugi.bio/atlas/disease/palmoplantar-keratoderma-esophageal-carcinoma-syndrome/).

**Reported phenotype names (ClinVar):** Palmoplantar keratoderma-esophageal carcinoma syndrome, not provided, not specified, none provided, AllHighlyPenetrant, PALMOPLANTAR KERATODERMA WITH ESOPHAGEAL CANCER, KERATOSIS PALMARIS ET PLANTARIS WITH ESOPHAGEAL CANCER, Tylosis with Esophageal Cancer.

## Similar variants {#similar}

Related RHBDF2 variant pages (same residue, condition, or type): [RHBDF2 p.Ile157Thr](/variant/rhbdf2-p-ile157thr), [RHBDF2 c.151-27G>T](/variant/rhbdf2-c-151-minus-27g-t), [RHBDF2 c.151-86G>A](/variant/rhbdf2-c-151-minus-86g-a), [RHBDF2 p.Ala397Ser](/variant/rhbdf2-p-ala397ser), [RHBDF2 p.Ala725Val](/variant/rhbdf2-p-ala725val), [RHBDF2 p.Arg113His](/variant/rhbdf2-p-arg113his), [RHBDF2 p.Arg235Trp](/variant/rhbdf2-p-arg235trp), [RHBDF2 p.Arg237Trp](/variant/rhbdf2-p-arg237trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 325427). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*