# NM_001130438.3(SPTAN1):c.2177A>T (p.Asp726Val)

https://sugi.bio/variant/sptan1-p-asp726val

## Summary

**SPTAN1 p.Asp726Val (c.2177A>T)** is classified **Uncertain significance** in SPTAN1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.995); Very rare (popmax 0.0022%, sas); Associated with early-infantile DEE.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2541186950 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the SPTAN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to early-infantile DEE.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027299/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SPTAN1](https://sugi.bio/atlas/gene/SPTAN1/) |
| Protein change (HGVS p.) | p.Asp726Val |
| Coding change (HGVS c.) | c.2177A>T |
| MANE Select transcript | [NM_001130438](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130438) |
| dbSNP | [rs2541186950](https://www.ncbi.nlm.nih.gov/snp/rs2541186950/) |
| Variant type | single nucleotide variant |
| Location | chr9:128583953-128583953 (GRCh38) |
| ClinVar | [VCV2664680](https://www.ncbi.nlm.nih.gov/clinvar/variation/2664680/) |

**All HGVS expressions:** `NC_000009.11:g.131346232A>T`, `NC_000009.12:g.128583953A>T`, `NG_027748.1:g.36396A>T`, `NG_027748.2:g.36368A>T`, `NM_001130438.3:c.2177A>T`, `NM_001195532.2:c.2177A>T`, `NM_001363759.2:c.2177A>T`, `NM_001363765.2:c.2177A>T`, `NM_001375310.1:c.2177A>T`, `NM_001375311.2:c.2177A>T`, `NM_001375312.2:c.2213A>T`, `NM_001375313.1:c.2177A>T`, `NM_001375314.2:c.2177A>T`, `NM_001375318.1:c.2213A>T`, `NM_003127.4:c.2177A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.995)
- REVEL 0.671 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.248 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.089, GERP 2, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.0**. 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 0.68** across the covering region of the MANE Select transcript (128,566,741–128,604,398), spanning 37,657 bp. Chi-square p 1.9e-36. 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 (A>G, Δ0.33 donor 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 **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000136% · 2/91,086 in the highest group · 2/1,614,188 alleles overall — very rare (popmax 0.0022%, sas).

*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}

**SPTAN1** population constraint: LOEUF 0.222, pLI 1, missense-Z 7.9475; ClinGen dosage — haploinsufficiency 3/3, 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):

- **genetic developmental and epileptic encephalopathy** — Definitive (AD)

## Protein context {#protein}

Residue **726** lies in a UniProt-annotated variant site (in hmnd11; pathogenic; decreased protein levels in patient cells); a UniProt-annotated variant site (in devep; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 77.05, 4% of residues very-high.

**7 experimental structure(s)** (PDB): [2FOT](https://www.rcsb.org/structure/2FOT), [3F31](https://www.rcsb.org/structure/3F31), [3FB2](https://www.rcsb.org/structure/3FB2), [5FW9](https://www.rcsb.org/structure/5FW9), [5FWB](https://www.rcsb.org/structure/5FWB), [5FWC](https://www.rcsb.org/structure/5FWC).

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

*Describes the biological roles of SPTAN1 (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:** SPTAN1's established molecular role includes cadherin binding.


### Pathways affected {#pathways}

SPTAN1 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | curated |
| [RHOV GTPase cycle](https://reactome.org/content/detail/R-HSA-9013424) | 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 |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

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

**Molecular function:** cadherin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-03.

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

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Uncertain significance | no assertion criteria provided | clinical testing | 2021-03-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-03 |

## Associated conditions {#conditions}

[early-infantile DEE](https://sugi.bio/atlas/disease/early-infantile-dee/).

**Reported phenotype names (ClinVar):** Early-infantile DEE, not provided, Ohtahara syndrome, Early infantile epileptic encephalopathy, Early infantile epileptic encephalopathy with suppression bursts, none provided.

## Similar variants {#similar}

Related SPTAN1 variant pages (same residue, condition, or type): [SPTAN1 p.Arg2308Cys](/variant/sptan1-p-arg2308cys), [SPTAN1 p.Arg548Ter](/variant/sptan1-p-arg548ter), [SPTAN1 p.Glu2271Lys](/variant/sptan1-p-glu2271lys), [SPTAN1 c.1572+5G>C](/variant/sptan1-c-1572-plus-5g-c), [SPTAN1 c.3156-11C>G](/variant/sptan1-c-3156-minus-11c-g), [SPTAN1 c.3519+5G>T](/variant/sptan1-c-3519-plus-5g-t), [SPTAN1 c.4758+3A>C](/variant/sptan1-c-4758-plus-3a-c), [SPTAN1 c.5600+5G>A](/variant/sptan1-c-5600-plus-5g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2664680). 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.*