# NM_001005498.4(RHBDF2):c.70C>T (p.Pro24Ser)

https://sugi.bio/variant/rhbdf2-p-pro24ser

## Summary

**RHBDF2 p.Pro24Ser (c.70C>T)** is classified **Uncertain significance** in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-29). AlphaMissense: likely pathogenic (0.5776); Very rare (popmax 0.00167%, amr); Associated with palmoplantar keratoderma-esophageal carcinoma syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1567881128 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the RHBDF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Pro24Ser |
| Coding change (HGVS c.) | c.70C>T |
| MANE Select transcript | [NM_001005498](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005498) |
| dbSNP | [rs1567881128](https://www.ncbi.nlm.nih.gov/snp/rs1567881128/) |
| Variant type | single nucleotide variant |
| Location | chr17:76481455-76481455 (GRCh38) |
| ClinVar | [VCV3240315](https://www.ncbi.nlm.nih.gov/clinvar/variation/3240315/) |

**All HGVS expressions:** `LRG_532:g.24973C>T`, `LRG_532t1:c.70C>T`, `NC_000017.10:g.74477537G>A`, `NC_000017.11:g.76481455G>A`, `NG_032852.1:g.24973C>T`, `NM_001005498.4:c.70C>T`, `NM_001376228.1:c.70C>T`, `NM_001376229.1:c.70C>T`, `NM_001376230.1:c.70C>T`, `NM_024599.5:c.70C>T`, `NR_164785.1:n.719C>T`, `NR_164786.1:n.461C>T`, `NR_164787.1:n.777C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5776)
- REVEL 0.366 (indeterminate)
- SaProt LLR -7.151 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 11.613, GERP 1.59, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.3**. 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.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (76,474,058–76,481,524), spanning 7,466 bp. Chi-square p 2.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00167%** (amr) · 1/60,026 in the highest group · 1/1,460,342 alleles overall — very rare (popmax 0.00167%, amr).

*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, triplosensitivity 0 (0–3 scale). *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 **24** lies in the 'disordered' region.

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:** p.Pro24Ser falls in the disordered region. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-29 |

## 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, KERATOSIS PALMARIS ET PLANTARIS WITH ESOPHAGEAL CANCER, Tylosis with Esophageal Cancer, PALMOPLANTAR KERATODERMA 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 2026-07-14); 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 3240315). 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.*