# NM_000337.6(SGCD):c.289C>T (p.Arg97Ter)

https://sugi.bio/variant/sgcd-p-arg97ter

## Summary

**SGCD p.Arg97Ter (c.289C>T)** is classified **Pathogenic** in SGCD (ClinVar, Expert panel, 5 submitters; last evaluated 2025-01-08). Very rare (popmax 0.00115%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs758700138 · 5 submitters · 3 linked conditions · very rare (popmax 0.00115%, sas)

## For patients & families {#patients}

This is a change in the SGCD gene that is considered disease-causing, submitted by 5 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019825/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SGCD](https://sugi.bio/atlas/gene/SGCD/) |
| Protein change (HGVS p.) | p.Arg97Ter |
| Coding change (HGVS c.) | c.289C>T |
| MANE Select transcript | [NM_000337](https://www.ncbi.nlm.nih.gov/nuccore/NM_000337) |
| dbSNP | [rs758700138](https://www.ncbi.nlm.nih.gov/snp/rs758700138/) |
| Variant type | single nucleotide variant |
| Location | chr5:156508697-156508697 (GRCh38) |
| ClinVar | [VCV1677453](https://www.ncbi.nlm.nih.gov/clinvar/variation/1677453/) |

**All HGVS expressions:** `LRG_205:g.643354C>T`, `NC_000005.10:g.156508697C>T`, `NC_000005.9:g.155935707C>T`, `NG_008693.2:g.643354C>T`, `NM_000337.6:c.289C>T`, `NM_001128209.2:c.286C>T`, `NM_172244.3:c.289C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 3.517, GERP 0.153, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.88, pLI 0.054132. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. 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.*
- 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 **0.00115%** (sas) · 1/87,260 in the highest group · 1/1,575,052 alleles overall — very rare (popmax 0.00115%, 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}

**SGCD** population constraint: LOEUF 0.88, pLI 0.054132, missense-Z -0.11017. *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):

- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)
- **dilated cardiomyopathy 1L** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.43, 27% of residues very-high.

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

*Describes the biological roles of SGCD (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-08.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2021–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Limb Girdle Muscular Dystrophy VCEP (autosomal recessive limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM3_Supporting`, `PM2_Supporting`, `PP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000337.6: c.289C>T p.(Arg97Ter) variant in SGCD is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/9, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in a homozygous state in at least two patients with LGMD who were from consanguineous families (0.5 pts, PMID: 34515763, 30733730; PM3_Supporting). At least one of these patients displayed progressive limb girdle weakness observed over more than six months (PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001146 (1/87260 alleles) in the South Asian population, which is lower than the ClinGen LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-01-08 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/ce1b25c2-4939-4be5-a164-23a81edf121e).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-03 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2025-01-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-14 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-06 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/), [autosomal recessive limb-girdle muscular dystrophy type 2F](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2f/), [dilated cardiomyopathy 1L](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1l/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, not provided, Dilated cardiomyopathy 1L, Autosomal recessive limb-girdle muscular dystrophy type 2F, none provided, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 6, Muscular dystrophy limb-girdle with delta-sarcoglyan deficiency.

## Similar variants {#similar}

Related SGCD variant pages (same residue, condition, or type): [SGCD p.Arg97Gln](/variant/sgcd-p-arg97gln), [SGCD p.Arg97=](/variant/sgcd-p-arg97), [SGCD p.Arg165Ter](/variant/sgcd-p-arg165ter), [SGCD p.Arg31Gly](/variant/sgcd-p-arg31gly), [SGCD p.Arg31Trp](/variant/sgcd-p-arg31trp), [SGCD p.Ile64Thr](/variant/sgcd-p-ile64thr), [SGCD c.192+1G>A](/variant/sgcd-c-192-plus-1g-a), [SGCD c.294+1G>A](/variant/sgcd-c-294-plus-1g-a).

### 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 1677453). 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.*