# NM_000023.4(SGCA):c.600G>A (p.Val200=)

https://sugi.bio/variant/sgca-p-val200

## Summary

**SGCA p.Val200= (c.600G>A)** is classified **Conflicting classifications of pathogenicity** in SGCA (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-09-23). Very rare (popmax 0.00667%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2D.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs764188161 · 5 submitters · 1 linked condition · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the SGCA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2D.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Prevalence | <1 / 1 000 000 (United Kingdom) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SGCA is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Achilles tendon contracture — Frequent (79-30%)
- Frequent falls — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Hyperlordosis — Frequent (79-30%)
- Gowers sign — Frequent (79-30%)
- Difficulty climbing stairs — Frequent (79-30%)
- Muscular dystrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000438/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.Val200= |
| Coding change (HGVS c.) | c.600G>A |
| MANE Select transcript | [NM_000023](https://www.ncbi.nlm.nih.gov/nuccore/NM_000023) |
| dbSNP | [rs764188161](https://www.ncbi.nlm.nih.gov/snp/rs764188161/) |
| Variant type | single nucleotide variant |
| Location | chr17:50169107-50169107 (GRCh38) |
| ClinVar | [VCV390366](https://www.ncbi.nlm.nih.gov/clinvar/variation/390366/) |

**All HGVS expressions:** `LRG_203:g.8103G>A`, `LRG_203t1:c.600G>A`, `NC_000017.10:g.48246468G>A`, `NC_000017.11:g.50169107G>A`, `NG_008889.1:g.8103G>A`, `NM_000023.4:c.600G>A`, `NM_001135697.3:c.584+535G>A`, `NR_135553.2:n.636G>A`

## 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 gain** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 5.183, GERP 0.418, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.99**. 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 **0.00**, acceptor gain **0.01**, donor gain **0.31**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.31**.
- Pangolin: Δ**0.30** (loss), gain 0.12 / loss 0.30. SpliceAI calls gain. 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): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/59,994 in the highest group · 5/1,613,760 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 14,999 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-09-23.

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

**Submission history:** 5 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Hadassah Hebrew University Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-01-10 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-11-08 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2023-02-08 |

## Associated conditions {#conditions}

[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 type 2D, not specified, AllHighlyPenetrant, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 3, ADHALINOPATHY, PRIMARY, DUCHENNE-LIKE AUTOSOMAL RECESSIVE MUSCULAR DYSTROPHY, TYPE 2.

## Similar variants {#similar}

Related SGCA variant pages (same residue, condition, or type): [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.Arg221Cys](/variant/sgca-p-arg221cys), [SGCA p.Arg221Pro](/variant/sgca-p-arg221pro), [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 390366). 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.*