# NM_000023.4(SGCA):c.613C>T (p.Pro205Ser)

https://sugi.bio/variant/sgca-p-pro205ser

## Summary

**SGCA p.Pro205Ser (c.613C>T)** is classified **Pathogenic** in SGCA (ClinVar, Expert panel, 1 submitter; last evaluated 2026-04-29). AlphaMissense: likely benign (0.1302); Very rare (popmax 0.0011%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the SGCA gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 1 submitter, 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.Pro205Ser |
| Coding change (HGVS c.) | c.613C>T |
| MANE Select transcript | [NM_000023](https://www.ncbi.nlm.nih.gov/nuccore/NM_000023) |
| Variant type | single nucleotide variant |
| Location | chr17:50169120-50169120 (GRCh38) |
| ClinVar | [VCV4849940](https://www.ncbi.nlm.nih.gov/clinvar/variation/4849940/) |

**All HGVS expressions:** `LRG_203:g.8116C>T`, `LRG_203t1:c.613C>T`, `NC_000017.10:g.48246481C>T`, `NC_000017.11:g.50169120C>T`, `NG_008889.1:g.8116C>T`, `NM_000023.4:c.613C>T`, `NM_001135697.3:c.584+548C>T`, `NR_135553.2:n.649C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1302) — ⚠ discordant with the pathogenic call
- REVEL 0.815 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.472 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 7.64, GERP 1.51, phastCons 1 — highly conserved (differs from AlphaMissense)
- 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, C>G, IS in the release and scores Δ0.49 acceptor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,088 in the highest group · 1/1,613,960 alleles overall — very rare (popmax 0.0011%, 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}

**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}

Residue **205** lies in a UniProt-annotated variant site (in lgmdr3).

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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-04-29.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2026-04-29 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy.

## Same-residue context {#hotspot}

Residue **205** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SGCA p.Pro205His](/variant/sgca-p-pro205his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SGCA variant pages (same residue, condition, or type): [SGCA p.Pro205His](/variant/sgca-p-pro205his), [SGCA p.Pro205Leu](/variant/sgca-p-pro205leu), [SGCA p.Pro205=](/variant/sgca-p-pro205), [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).

### 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 4849940). 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.*