# NM_000023.4(SGCA):c.662G>C (p.Arg221Pro)

https://sugi.bio/variant/sgca-p-arg221pro

## Summary

**SGCA p.Arg221Pro (c.662G>C)** is classified **Likely pathogenic** in SGCA (ClinVar, Expert panel, 4 submitters; last evaluated 2025-01-07). AlphaMissense: likely pathogenic (0.6996); Very rare (popmax 6.2e-05%); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs138254713 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the SGCA gene that is considered likely disease-causing, submitted by 4 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 | [SGCA](https://sugi.bio/atlas/gene/SGCA/) |
| Protein change (HGVS p.) | p.Arg221Pro |
| Coding change (HGVS c.) | c.662G>C |
| MANE Select transcript | [NM_000023](https://www.ncbi.nlm.nih.gov/nuccore/NM_000023) |
| dbSNP | [rs138254713](https://www.ncbi.nlm.nih.gov/snp/rs138254713/) |
| Variant type | single nucleotide variant |
| Location | chr17:50169169-50169169 (GRCh38) |
| ClinVar | [VCV497670](https://www.ncbi.nlm.nih.gov/clinvar/variation/497670/) |

**All HGVS expressions:** `LRG_203:g.8165G>C`, `LRG_203t1:c.662G>C`, `NC_000017.10:g.48246530G>C`, `NC_000017.11:g.50169169G>C`, `NG_008889.1:g.8165G>C`, `NM_000023.2:c.662G>C`, `NM_000023.3:c.662G>C`, `NM_000023.4:c.662G>C`, `NM_001135697.3:c.584+597G>C`, `NR_135553.2:n.698G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6996) — concordant with the pathogenic call
- REVEL 0.765 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.22 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.894, GERP 1.51, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.5**. 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 0.91** across the covering region of the MANE Select transcript (50,166,041–50,175,434), spanning 9,393 bp. Chi-square p 0.033. 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 (G>T, Δ0.35 acceptor 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): global (via dbSNP) **6.2e-05%** · 1/1,613,916 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}

**SGCA** population constraint: LOEUF 1.273, pLI 9.5209e-12, missense-Z 0.64856. *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)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.15, 47% of residues very-high.

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

*Describes the biological roles of SGCA (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}

SGCA 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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-07.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely Pathogenic).

**Submission history:** 4 submissions (2016–2025); classifications have differed over time.

**ClinGen expert panel:** Likely 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):** `PM2_Supporting`, `PP4_Strong`, `PP3`, `PM3`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `BS2`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000023.4: c.662G>C variant in SGCA is a missense variant predicted to cause substitution of arginine by proline at amino acid 221 (p.Arg221Pro). This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely 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; 01/07/2025): PM2_Supporting, PP3, PM3, PP4_Strong.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-01-07 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/e203815d-e310-4737-9fca-d20939ca73c3).*
*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 |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-10 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-01-07 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-01-29 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-02-20 |

## 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 2D](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2d/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, not provided, Autosomal recessive limb-girdle muscular dystrophy type 2D, none provided, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 3, ADHALINOPATHY, PRIMARY, DUCHENNE-LIKE AUTOSOMAL RECESSIVE MUSCULAR DYSTROPHY, TYPE 2.

## Same-residue context {#hotspot}

Residue **221** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SGCA p.Arg221Cys](/variant/sgca-p-arg221cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SGCA variant pages (same residue, condition, or type): [SGCA p.Arg221Cys](/variant/sgca-p-arg221cys), [SGCA p.Arg221His](/variant/sgca-p-arg221his), [SGCA c.37+6T>C](/variant/sgca-c-37-plus-6t-c), [SGCA c.585-1G>A](/variant/sgca-c-585-minus-1g-a), [SGCA c.957-11C>G](/variant/sgca-c-957-minus-11c-g), [SGCA p.Ala107Val](/variant/sgca-p-ala107val), [SGCA p.Arg192Ter](/variant/sgca-p-arg192ter), [SGCA p.Arg284Cys](/variant/sgca-p-arg284cys).

### 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 497670). 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.*