# NM_001005498.4(RHBDF2):c.2109C>T (p.Phe703=)

https://sugi.bio/variant/rhbdf2-p-phe703

## Summary

**RHBDF2 p.Phe703= (c.2109C>T)** is classified **Likely benign** in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). Very rare (popmax 0.00807%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00807%, afr)

## For patients & families {#patients}

This is a change in the RHBDF2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Phe703= |
| Coding change (HGVS c.) | c.2109C>T |
| MANE Select transcript | [NM_001005498](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005498) |
| Variant type | single nucleotide variant |
| Location | chr17:76472008-76472008 (GRCh38) |
| ClinVar | [VCV3609712](https://www.ncbi.nlm.nih.gov/clinvar/variation/3609712/) |

**All HGVS expressions:** `LRG_532:g.34420C>T`, `LRG_532t1:c.2196C>T`, `NC_000017.10:g.74468090G>A`, `NC_000017.11:g.76472008G>A`, `NG_015976.1:g.23658G>A`, `NG_032852.1:g.34420C>T`, `NM_001005498.4:c.2109C>T`, `NM_001376228.1:c.2109C>T`, `NM_001376229.1:c.2109C>T`, `NM_001376230.1:c.2109C>T`, `NM_024599.5:c.2196C>T`, `NR_164785.1:n.2828C>T`, `NR_164786.1:n.2570C>T`, `NR_164787.1:n.2886C>T`

## 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 -0.288, GERP -1.92, phastCons 0.01 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 13.59**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.64 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00807%** (afr) · FAF95 0.00349% · FAF99 0.0024% · 6/74,358 in the highest group · 23/1,575,982 alleles overall — very rare (popmax 0.00807%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0164% | 6,110 |
| African / African-American (grpmax) | 0.00807% | 12,393 |
| Admixed American | 0.00185% | 53,944 |
| Finnish (not grpmax-eligible) | 0.00165% | 60,424 |
| European (non-Finnish) | 0.000431% | 232,146 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*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 **703** lies in an α-helix.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-18.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-18 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## 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.Ala700Thr](/variant/rhbdf2-p-ala700thr), [RHBDF2 p.Ala725Val](/variant/rhbdf2-p-ala725val), [RHBDF2 p.Arg113His](/variant/rhbdf2-p-arg113his), [RHBDF2 p.Arg205His](/variant/rhbdf2-p-arg205his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3609712). 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.*