# NM_001376013.1(EPB41):c.776C>T (p.Ala259Val)

https://sugi.bio/variant/epb41-p-ala259val

## Summary

**EPB41 p.Ala259Val (c.776C>T)** is classified **Uncertain significance** in EPB41 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-03). AlphaMissense: likely benign (0.0729); Very rare (popmax 0.000512%, nfe); Associated with elliptocytosis 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2149686920 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000512%, nfe)

## For patients & families {#patients}

This is a change in the EPB41 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to elliptocytosis 1.

*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 (Worldwide) |
| Diagnostic panels | EPB41 is a diagnostic-grade gene on 2 Genomics England panels |

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

- Abnormal erythrocyte morphology — Obligate (100%)
- Elliptocytosis — Frequent (79-30%)
- Increased red cell osmotic fragility — Frequent (79-30%)
- Jaundice — Occasional (29-5%)
- Splenomegaly — Occasional (29-5%)
- Hemolytic anemia — Occasional (29-5%)
- Reticulocytosis — Occasional (29-5%)
- Hyperbilirubinemia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015528/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EPB41](https://sugi.bio/atlas/gene/EPB41/) |
| Protein change (HGVS p.) | p.Ala259Val |
| Coding change (HGVS c.) | c.776C>T |
| MANE Select transcript | [NM_001376013](https://www.ncbi.nlm.nih.gov/nuccore/NM_001376013) |
| dbSNP | [rs2149686920](https://www.ncbi.nlm.nih.gov/snp/rs2149686920/) |
| Variant type | single nucleotide variant |
| Location | chr1:28997309-28997309 (GRCh38) |
| ClinVar | [VCV1476745](https://www.ncbi.nlm.nih.gov/clinvar/variation/1476745/) |

**All HGVS expressions:** `NC_000001.10:g.29323821C>T`, `NC_000001.11:g.28997309C>T`, `NG_013344.1:g.115219C>T`, `NM_001166005.2:c.776C>T`, `NM_001166006.2:c.776C>T`, `NM_001166007.2:c.149C>T`, `NM_001376013.1:c.776C>T`, `NM_001376014.1:c.776C>T`, `NM_001376015.1:c.776C>T`, `NM_001376016.1:c.776C>T`, `NM_001376017.1:c.776C>T`, `NM_001376018.1:c.776C>T`, `NM_001376019.1:c.776C>T`, `NM_001376020.1:c.776C>T`, `NM_001376021.1:c.776C>T`, `NM_001376022.1:c.149C>T`, `NM_001376023.1:c.149C>T`, `NM_001376024.1:c.149C>T`, `NM_001376025.1:c.149C>T`, `NM_001376026.1:c.149C>T`, `NM_001376027.1:c.149C>T`, `NM_001376028.1:c.149C>T`, `NM_004437.4:c.149C>T`, `NM_203342.3:c.149C>T`, `NM_203343.3:c.681+3767C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0729)
- REVEL 0.126 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.985 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.362, GERP -2.15 — weakly conserved position
- CADD: **PHRED 15.38**. 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 0.90** across the covering region of the MANE Select transcript (28,987,438–29,018,344), spanning 30,906 bp. Chi-square p 0.042. 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 **0.000512%** (nfe) · FAF95 0.000184% · FAF99 0.000121% · 6/1,172,378 in the highest group · 7/1,453,412 alleles overall — very rare (popmax 0.000512%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,196 |
| European (non-Finnish) (grpmax) | 0.000512% | 195,396 |

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}

**EPB41** population constraint: LOEUF 0.738, pLI 3.8406e-11, missense-Z 2.3584. *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 **259** lies in the ferm domain.

AlphaFold model confidence (whole protein): pLDDT 63.72, 31% of residues very-high.

**3 experimental structure(s)** (PDB): [1GG3](https://www.rcsb.org/structure/1GG3), [2RQ1](https://www.rcsb.org/structure/2RQ1), [3QIJ](https://www.rcsb.org/structure/3QIJ).

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

*Describes the biological roles of EPB41 (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:** EPB41's established molecular role includes structural constituent of cytoskeleton. p.Ala259Val falls in the ferm domain.


### Pathways affected {#pathways}

EPB41 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** structural constituent of cytoskeleton, 1-phosphatidylinositol binding, phosphoprotein binding.

**Biological process:** positive regulation of protein localization to cell cortex.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-12-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-04-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-03 |

## Associated conditions {#conditions}

[elliptocytosis 1](https://sugi.bio/atlas/disease/elliptocytosis-1/).

**Reported phenotype names (ClinVar):** Elliptocytosis 1, not provided, none provided, 4.1- TRAIT, 4.1-MINUS TRAIT, ELLIPTOCYTOSIS, RHESUS-LINKED TYPE, PROTEIN 4.1 OF ERYTHROCYTE MEMBRANE, DEFECT OF.

## Similar variants {#similar}

Related EPB41 variant pages (same residue, condition, or type): [EPB41 p.Arg471Ter](/variant/epb41-p-arg471ter), [EPB41 p.Arg554Ter](/variant/epb41-p-arg554ter), [EPB41 p.Arg715Ter](/variant/epb41-p-arg715ter), [EPB41 p.Gln274Ter](/variant/epb41-p-gln274ter), [EPB41 p.Tyr331Ter](/variant/epb41-p-tyr331ter), [EPB41 p.Ala502Val](/variant/epb41-p-ala502val), [EPB41 p.Ala535Val](/variant/epb41-p-ala535val), [EPB41 p.Ala683Pro](/variant/epb41-p-ala683pro).

### 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 1476745). 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.*