# NM_020971.3(SPTBN4):c.77A>T (p.Glu26Val)

https://sugi.bio/variant/sptbn4-p-glu26val

## Summary

**SPTBN4 p.Glu26Val (c.77A>T)** is classified **Uncertain significance** in SPTBN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.2956); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

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

## For patients & families {#patients}

This is a change in the SPTBN4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [SPTBN4](https://sugi.bio/atlas/gene/SPTBN4/) |
| Protein change (HGVS p.) | p.Glu26Val |
| Coding change (HGVS c.) | c.77A>T |
| MANE Select transcript | [NM_020971](https://www.ncbi.nlm.nih.gov/nuccore/NM_020971) |
| Variant type | single nucleotide variant |
| Location | chr19:40472698-40472698 (GRCh38) |
| ClinVar | [VCV3961664](https://www.ncbi.nlm.nih.gov/clinvar/variation/3961664/) |

**All HGVS expressions:** `NC_000019.10:g.40472698A>T`, `NC_000019.9:g.40978605A>T`, `NG_029905.2:g.10699A>T`, `NM_020971.3:c.77A>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** (0.2956)
- REVEL 0.425 (indeterminate)
- SaProt LLR -7.261 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.32) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 10.977, GERP 2.37, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.2**. 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 1.19** across the covering region of the MANE Select transcript (40,472,622–40,472,757), spanning 135 bp. Chi-square p 0.13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.32**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.32**.
- Pangolin: Δ**0.25** (gain), gain 0.25 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**SPTBN4** population constraint: LOEUF 0.529, pLI 1.3288e-05, missense-Z 0.64957. *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):

- **neurodevelopmental disorder with hypotonia, neuropathy, and deafness** — Definitive (AR)

## Protein context {#protein}

Residue **26** lies in the 'actin-binding' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.50, 9% of residues very-high.

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

*Describes the biological roles of SPTBN4 (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:** SPTBN4's established molecular role includes phosphatase binding. p.Glu26Val falls in the actin-binding region.


### Pathways affected {#pathways}

SPTBN4 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | electronic |

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

**Molecular function:** phosphatase binding, ankyrin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related SPTBN4 variant pages (same residue, condition, or type): [SPTBN4 p.Ala1083Gly](/variant/sptbn4-p-ala1083gly), [SPTBN4 p.Ala1134Val](/variant/sptbn4-p-ala1134val), [SPTBN4 p.Ala1993Val](/variant/sptbn4-p-ala1993val), [SPTBN4 p.Ala463Thr](/variant/sptbn4-p-ala463thr), [SPTBN4 p.Ala586Thr](/variant/sptbn4-p-ala586thr), [SPTBN4 p.Arg1365Trp](/variant/sptbn4-p-arg1365trp), [SPTBN4 p.Arg1534Trp](/variant/sptbn4-p-arg1534trp), [SPTBN4 p.Arg2006Gln](/variant/sptbn4-p-arg2006gln).

### 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 3961664). 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.*