# NM_001377540.1(SLMAP):c.2272A>T (p.Ser758Cys)

https://sugi.bio/variant/slmap-p-ser758cys

## Summary

**SLMAP p.Ser758Cys (c.2272A>T)** is classified **Likely benign** in SLMAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0695); Rare (popmax 0.251%, nfe); Associated with Brugada syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs143689400 · 3 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.251%, nfe)

## For patients & families {#patients}

This is a change in the SLMAP gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, 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.Ser758Cys |
| Coding change (HGVS c.) | c.2272A>T |
| MANE Select transcript | [NM_001377540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377540) |
| dbSNP | [rs143689400](https://www.ncbi.nlm.nih.gov/snp/rs143689400/) |
| Variant type | single nucleotide variant |
| Location | chr3:57917039-57917039 (GRCh38) |
| ClinVar | [VCV416638](https://www.ncbi.nlm.nih.gov/clinvar/variation/416638/) |

**All HGVS expressions:** `NC_000003.11:g.57902766A>T`, `NC_000003.12:g.57917039A>T`, `NG_042789.1:g.164784A>T`, `NM_001304420.3:c.2221A>T`, `NM_001304421.2:c.2107A>T`, `NM_001304422.3:c.823A>T`, `NM_001304423.3:c.625A>T`, `NM_001311178.2:c.823A>T`, `NM_001311179.2:c.700A>T`, `NM_001377538.1:c.2293A>T`, `NM_001377539.1:c.2272A>T`, `NM_001377540.1:c.2272A>T`, `NM_001377541.1:c.2221A>T`, `NM_001377542.1:c.2221A>T`, `NM_001377545.1:c.2209A>T`, `NM_001377549.1:c.2170A>T`, `NM_001377551.1:c.2158A>T`, `NM_001377552.1:c.2158A>T`, `NM_001377555.1:c.2149A>T`, `NM_001377557.1:c.2107A>T`, `NM_001377559.1:c.2107A>T`, `NM_001377562.1:c.2098A>T`, `NM_001377921.1:c.2098A>T`, `NM_001377922.1:c.2086A>T`, `NM_001377923.1:c.2047A>T`, `NM_001377924.1:c.2035A>T`, `NM_001377925.1:c.1984A>T`, `NM_001377926.1:c.700A>T`, `NM_001377927.1:c.700A>T`, `NM_007159.4:c.2170A>T`, `NM_007159.5:c.2170A>T`, `NR_165328.1:n.3316A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0695)
- REVEL 0.151 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.575 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.866, GERP 0.087, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S741C** vs ClinVar **S758C**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 22.1**. 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 0.85** across the covering region of the MANE Select transcript (57,831,510–57,925,925), spanning 94,415 bp. Chi-square p 9.6e-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 (A>G, Δ0.84 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 **0.251%** (nfe) · FAF95 0.244% · FAF99 0.241% · 2,965/1,179,922 in the highest group · 3,231/1,613,986 alleles overall — rare (popmax 0.251%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.251% | 398 |
| Remaining individuals (not grpmax-eligible) | 0.162% | 619 |
| Admixed American | 0.08% | 1,250 |
| South Asian | 0.0714% | 1,401 |
| African / African-American | 0.036% | 2,780 |
| Finnish (not grpmax-eligible) | 0.0359% | 2,784 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,592 |
| East Asian | 0.00223% | 44,806 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 5 submissions (2023–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-10 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Brugada syndrome, not specified, Colorectal cancer, Thyroid cancer, nonmedullary, 1, Lung cancer, AllHighlyPenetrant, Sudden unexplained nocturnal death syndrome, Sudden Unexplained Death Syndrome, Sudden Unexplained Nocturnal Death Syndrome (SUNDS), Sudden unexpected nocturnal death syndrome.

## 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 416638). 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.*