# NM_000023.4(SGCA):c.406G>C (p.Ala136Pro)

https://sugi.bio/variant/sgca-p-ala136pro

## Summary

**SGCA p.Ala136Pro (c.406G>C)** is classified **Uncertain significance** in SGCA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely pathogenic (0.9794); Very rare (popmax 8.58e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2D.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.58e-05%, nfe)

## For patients & families {#patients}

This is a change in the SGCA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Ala136Pro |
| Coding change (HGVS c.) | c.406G>C |
| MANE Select transcript | [NM_000023](https://www.ncbi.nlm.nih.gov/nuccore/NM_000023) |
| Variant type | single nucleotide variant |
| Location | chr17:50168394-50168394 (GRCh38) |
| ClinVar | [VCV4061272](https://www.ncbi.nlm.nih.gov/clinvar/variation/4061272/) |

**All HGVS expressions:** `LRG_203:g.7390G>C`, `LRG_203t1:c.406G>C`, `NC_000017.10:g.48245755G>C`, `NC_000017.11:g.50168394G>C`, `NG_008889.1:g.7390G>C`, `NM_000023.4:c.406G>C`, `NM_001135697.3:c.406G>C`, `NR_135553.2:n.442G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9794)
- REVEL 0.955 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.411 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.696, GERP 1.39, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in SGCA (of 2,257 modeled).
- CADD: **PHRED 29.8**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **8.58e-05%** (nfe) · 1/1,165,766 in the highest group · 1/1,585,208 alleles overall — very rare (popmax 8.58e-05%, nfe).

*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 **136** lies in a UniProt-annotated variant site (in lgmdr3; associated with g-137).

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}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2025-05-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-05-28 |

## 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, ADHALINOPATHY, PRIMARY, DUCHENNE-LIKE AUTOSOMAL RECESSIVE MUSCULAR DYSTROPHY, TYPE 2, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 3.

## Same-residue context {#hotspot}

Residue **136** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SGCA p.Ala136Thr](/variant/sgca-p-ala136thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SGCA variant pages (same residue, condition, or type): [SGCA p.Ala136Thr](/variant/sgca-p-ala136thr), [SGCA p.Ala136=](/variant/sgca-p-ala136), [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 4061272). 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.*