# NM_001114134.2(EPB42):c.1100C>G (p.Pro367Arg)

https://sugi.bio/variant/epb42-p-pro367arg

## Summary

**EPB42 p.Pro367Arg (c.1100C>G)** is classified **Uncertain significance** in EPB42 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). AlphaMissense: likely pathogenic (0.737); Absent from gnomAD v4.1; Associated with hereditary spherocytosis type 5.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EPB42 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hereditary spherocytosis type 5.

*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, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Germany) |
| Diagnostic panels | EPB42 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Hereditary spherocytosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Increased red cell osmotic fragility — Very frequent (99-80%)
- Jaundice — Frequent (79-30%)
- Pallor — Frequent (79-30%)
- Cholelithiasis — Frequent (79-30%)
- Muscle weakness — Frequent (79-30%)
- Splenomegaly — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Reticulocytosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015578/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EPB42](https://sugi.bio/atlas/gene/EPB42/) |
| Protein change (HGVS p.) | p.Pro367Arg |
| Coding change (HGVS c.) | c.1100C>G |
| MANE Select transcript | [NM_001114134](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114134) |
| Variant type | single nucleotide variant |
| Location | chr15:43207417-43207417 (GRCh38) |
| ClinVar | [VCV4078602](https://www.ncbi.nlm.nih.gov/clinvar/variation/4078602/) |

**All HGVS expressions:** `LRG_1171:g.23440C>G`, `LRG_1171t1:c.1190C>G`, `NC_000015.10:g.43207417G>C`, `NC_000015.9:g.43499615G>C`, `NG_011505.2:g.23440C>G`, `NM_000119.3:c.1190C>G`, `NM_001114134.2:c.1100C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.737)
- REVEL 0.568 (indeterminate)
- SaProt LLR -14.851 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.769, GERP 1.89, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in EPB42 (of 4,039 modeled).
- CADD: **PHRED 25.3**. 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 (43,197,305–43,220,825), spanning 23,520 bp. Chi-square p 3.5e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.31 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**EPB42** population constraint: LOEUF 0.771, pLI 1.1421e-09, missense-Z 2.2129; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}

Residue **367** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.35, 69% of residues very-high.

**13 experimental structure(s)** (PDB): [7TVZ](https://www.rcsb.org/structure/7TVZ), [7TW0](https://www.rcsb.org/structure/7TW0), [7TW1](https://www.rcsb.org/structure/7TW1), [7TW3](https://www.rcsb.org/structure/7TW3), [7TW5](https://www.rcsb.org/structure/7TW5), [7TW6](https://www.rcsb.org/structure/7TW6).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |

## Associated conditions {#conditions}

[hereditary spherocytosis type 5](https://sugi.bio/atlas/disease/hereditary-spherocytosis-type-5/).

**Reported phenotype names (ClinVar):** Hereditary spherocytosis type 5, EPB42-Related Hereditary Spherocytosis, EPB42-Related Spherocytosis.

## Similar variants {#similar}

Related EPB42 variant pages (same residue, condition, or type): [EPB42 p.Pro367Leu](/variant/epb42-p-pro367leu), [EPB42 p.Arg259Ter](/variant/epb42-p-arg259ter), [EPB42 p.Arg310Gln](/variant/epb42-p-arg310gln), [EPB42 c.10+51G>A](/variant/epb42-c-10-plus-51g-a), [EPB42 p.Ala353Val](/variant/epb42-p-ala353val), [EPB42 p.Ala51Thr](/variant/epb42-p-ala51thr), [EPB42 p.Ala566Thr](/variant/epb42-p-ala566thr), [EPB42 p.Arg155Cys](/variant/epb42-p-arg155cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 4078602). 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.*