# NM_001377540.1(SLMAP):c.1269C>T (p.Cys423=)

https://sugi.bio/variant/slmap-p-cys423

## Summary

**SLMAP p.Cys423= (c.1269C>T)** is classified **Likely benign** in SLMAP (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-13). Very rare (popmax 6.2e-05%); Associated with Brugada syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs2095482597 · 1 submitter · 1 linked condition · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the SLMAP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Brugada syndrome.

*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, Not applicable |
| Age of onset (of this condition) | Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 44 registered for this condition — see ClinicalTrials.gov |

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

- Syncope — Frequent (79-30%)
- Cardiac arrest — Frequent (79-30%)
- Right bundle branch block — Frequent (79-30%)
- ST segment elevation — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)
- Ventricular fibrillation — Occasional (29-5%)
- Paroxysmal ventricular tachycardia — Occasional (29-5%)
- Supraventricular tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001030/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLMAP](https://sugi.bio/atlas/gene/SLMAP/) |
| Protein change (HGVS p.) | p.Cys423= |
| Coding change (HGVS c.) | c.1269C>T |
| MANE Select transcript | [NM_001377540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377540) |
| dbSNP | [rs2095482597](https://www.ncbi.nlm.nih.gov/snp/rs2095482597/) |
| Variant type | single nucleotide variant |
| Location | chr3:57871667-57871667 (GRCh38) |
| ClinVar | [VCV1086682](https://www.ncbi.nlm.nih.gov/clinvar/variation/1086682/) |

**All HGVS expressions:** `NC_000003.11:g.57857394C>T`, `NC_000003.12:g.57871667C>T`, `NG_042789.1:g.119412C>T`, `NM_001304420.3:c.1218C>T`, `NM_001304421.2:c.1135+6951C>T`, `NM_001377538.1:c.1269C>T`, `NM_001377539.1:c.1269C>T`, `NM_001377540.1:c.1269C>T`, `NM_001377541.1:c.1218C>T`, `NM_001377542.1:c.1218C>T`, `NM_001377545.1:c.1237+6375C>T`, `NM_001377549.1:c.1167C>T`, `NM_001377551.1:c.1186+6810C>T`, `NM_001377552.1:c.1186+6810C>T`, `NM_001377555.1:c.1269C>T`, `NM_001377557.1:c.1135+6951C>T`, `NM_001377559.1:c.1135+6951C>T`, `NM_001377562.1:c.1218C>T`, `NM_001377921.1:c.1218C>T`, `NM_001377922.1:c.1237+6375C>T`, `NM_001377923.1:c.1167C>T`, `NM_001377924.1:c.1186+6810C>T`, `NM_001377925.1:c.1135+6951C>T`, `NM_007159.5:c.1167C>T`, `NR_165328.1:n.2311C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 4.556, GERP 2.35, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.08**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 31 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.20** (loss), gain 0.00 / loss 0.20. 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 (gnomAD v4.1): global (via dbSNP) **6.2e-05%** · 1/1,612,168 alleles overall — very rare (popmax 6.2e-05%).

*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}

**SLMAP** population constraint: LOEUF 0.531, pLI 0.85993, missense-Z 2.0271. *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):

- **Brugada syndrome** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.74, 42% of residues very-high.

**3 experimental structure(s)** (PDB): [6AKM](https://www.rcsb.org/structure/6AKM), [6AR0](https://www.rcsb.org/structure/6AR0), [6AR2](https://www.rcsb.org/structure/6AR2).

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

*Describes the biological roles of SLMAP (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:** SLMAP's established molecular role includes protein-macromolecule adaptor activity.


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

**Molecular function:** protein-macromolecule adaptor activity.

**Biological process:** negative regulation of hippo signaling, protein localization to plasma membrane, regulation of membrane depolarization during cardiac muscle cell action potential, regulation of sodium ion transmembrane transport.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-09-13.

**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 | 2020-09-13 |

## Associated conditions {#conditions}

[Brugada syndrome](https://sugi.bio/atlas/disease/brugada-syndrome/).

**Reported phenotype names (ClinVar):** Brugada syndrome, Sudden unexpected nocturnal death syndrome, Sudden unexplained nocturnal death syndrome, Sudden Unexplained Death Syndrome, Sudden Unexplained Nocturnal Death Syndrome (SUNDS).

## Similar variants {#similar}

Related SLMAP variant pages (same residue, condition, or type): [SLMAP c.*38C>T](/variant/slmap-c-star-38c-t), [SLMAP c.*55G>A](/variant/slmap-c-star-55g-a), [SLMAP c.*70G>A](/variant/slmap-c-star-70g-a), [SLMAP p.Ala365Asp](/variant/slmap-p-ala365asp), [SLMAP p.Ala506Ser](/variant/slmap-p-ala506ser), [SLMAP p.Ala597Val](/variant/slmap-p-ala597val), [SLMAP p.Arg136Gln](/variant/slmap-p-arg136gln), [SLMAP p.Arg138Cys](/variant/slmap-p-arg138cys).

### 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 1086682). 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.*