# NM_000023.4(SGCA):c.101G>A (p.Arg34His)

https://sugi.bio/variant/sgca-p-arg34his

## Summary

**SGCA p.Arg34His (c.101G>A)** is classified **Likely pathogenic** in SGCA (ClinVar, Expert panel, 17 submitters; last evaluated 2025-01-09). AlphaMissense: likely benign (0.072); Ultra-rare (popmax 0.0165%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs371675217 · 17 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the SGCA gene that is considered likely disease-causing, submitted by 17 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.Arg34His |
| Coding change (HGVS c.) | c.101G>A |
| MANE Select transcript | [NM_000023](https://www.ncbi.nlm.nih.gov/nuccore/NM_000023) |
| dbSNP | [rs371675217](https://www.ncbi.nlm.nih.gov/snp/rs371675217/) |
| Variant type | single nucleotide variant |
| Location | chr17:50167431-50167431 (GRCh38) |
| ClinVar | [VCV92301](https://www.ncbi.nlm.nih.gov/clinvar/variation/92301/) |

**All HGVS expressions:** `LRG_203:g.6427G>A`, `LRG_203t1:c.101G>A`, `NC_000017.10:g.48244792G>A`, `NC_000017.11:g.50167431G>A`, `NG_008889.1:g.6427G>A`, `NM_000023.3:c.101G>A`, `NM_000023.4:c.101G>A`, `NM_001135697.3:c.101G>A`, `NR_135553.2:n.137G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.072) — ⚠ discordant with the pathogenic call
- REVEL 0.708 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -6.732 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 3.841, GERP 0.15, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.6**. 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). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. 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. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. 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, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for SGCA (660 scored positions, the nearest 5 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *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 **0.0165%** (mid) · FAF95 0.0013% · FAF99 0.00108% · 1/6,062 in the highest group · 25/1,614,160 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| European (non-Finnish) | 0.00195% | 51,305 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |

*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 **34** 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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-09.

**Submitter consensus:** conflicting (16 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 17 submissions (2015–2025); 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:* `PM5`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000023.4: c.101G>A variant in SGCA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 34 (p.Arg34His). This variant has been detected in at least two individuals with autosomal recessive limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Arg77Cys, 1.0 pt, PMID: 18285821) (PM3). At least one patient with this variant and a second presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness as well as significantly reduced or absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 1828582). The filtering allele frequency of this variant is 0.000023 (the upper threshold of the 95% CI of 6/113724 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is lower than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.708, which is above the threshold of 0.7, 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; 01/09/2025): PP4_Strong, PM2_Supporting, PM3, PP3.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-01-09 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/5fe1934d-e35e-4f18-9095-389cc95f3639).*
*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 |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | research | 2024-03-17 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2015-12-15 |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-27 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-01-09 |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-08 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2016-07-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-16 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-19 |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2015-01-20 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-03 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Pathogenic | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-08 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-18 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-21 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |

## 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, SGCA-related disorder, SGCA-related condition, none provided, DUCHENNE-LIKE AUTOSOMAL RECESSIVE MUSCULAR DYSTROPHY, TYPE 2, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 3, ADHALINOPATHY, PRIMARY.

## Same-residue context {#hotspot}

Residue **34** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [SGCA p.Arg34Ser](/variant/sgca-p-arg34ser), [SGCA p.Arg34Cys](/variant/sgca-p-arg34cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SGCA variant pages (same residue, condition, or type): [SGCA p.Arg34Cys](/variant/sgca-p-arg34cys), [SGCA p.Arg34Ser](/variant/sgca-p-arg34ser), [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).

### 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 92301). 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.*