# NM_000337.6(SGCD):c.716C>T (p.Ala239Val)

https://sugi.bio/variant/sgcd-p-ala239val

## Summary

**SGCD p.Ala239Val (c.716C>T)** is classified **Uncertain significance** in SGCD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-02-08). AlphaMissense: likely benign (0.122); Ultra-rare (popmax 0.0111%, eas); Associated with dilated cardiomyopathy 1L.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs377153196 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0111%, eas)

## For patients & families {#patients}

This is a change in the SGCD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to dilated cardiomyopathy 1L.

*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 dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | SGCD is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Familial isolated dilated cardiomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Left ventricular systolic dysfunction — Very frequent (99-80%)
- Edema — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Arrhythmia — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Orthopnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015397/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SGCD](https://sugi.bio/atlas/gene/SGCD/) |
| Protein change (HGVS p.) | p.Ala239Val |
| Coding change (HGVS c.) | c.716C>T |
| MANE Select transcript | [NM_000337](https://www.ncbi.nlm.nih.gov/nuccore/NM_000337) |
| dbSNP | [rs377153196](https://www.ncbi.nlm.nih.gov/snp/rs377153196/) |
| Variant type | single nucleotide variant |
| Location | chr5:156759233-156759233 (GRCh38) |
| ClinVar | [VCV352336](https://www.ncbi.nlm.nih.gov/clinvar/variation/352336/) |

**All HGVS expressions:** `LRG_205:g.893891C>T`, `LRG_205t1:c.716C>T`, `NC_000005.10:g.156759233C>T`, `NC_000005.9:g.156186244C>T`, `NG_008693.2:g.893891C>T`, `NM_000337.6:c.716C>T`, `NM_001128209.2:c.713C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.122)
- REVEL 0.391 (indeterminate)
- SaProt LLR -8.291 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.016, GERP 0.738, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A238V** vs ClinVar **A239V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.0**. 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 1.12** across the covering region of the MANE Select transcript (156,329,577–156,759,387), spanning 429,810 bp. Chi-square p 0.031. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 16 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0111%** (eas) · FAF95 0.00434% · FAF99 0.00276% · 5/44,882 in the highest group · 49/1,613,452 alleles overall — ultra-rare (popmax 0.0111%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0574% | 1,741 |
| East Asian (grpmax) | 0.0111% | 8,976 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,226 |
| European (non-Finnish) | 0.00212% | 47,183 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**SGCD** population constraint: LOEUF 0.88, pLI 0.054132, missense-Z -0.11017. *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)
- **dilated cardiomyopathy 1L** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.43, 27% of residues very-high.

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

*Describes the biological roles of SGCD (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}

SGCD 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-02-08.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2018–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-15 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-08 |

## Associated conditions {#conditions}

[dilated cardiomyopathy 1L](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1l/), [autosomal recessive limb-girdle muscular dystrophy type 2F](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2f/), [qualitative or quantitative defects of delta-sarcoglycan](https://sugi.bio/atlas/disease/qualitative-or-quantitative-defects-of-delta-sarcoglycan/).

**Reported phenotype names (ClinVar):** Dilated cardiomyopathy 1L, Qualitative or quantitative defects of delta-sarcoglycan, Autosomal recessive limb-girdle muscular dystrophy type 2F, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 6, Muscular dystrophy limb-girdle with delta-sarcoglyan deficiency.

## Similar variants {#similar}

Related SGCD variant pages (same residue, condition, or type): [SGCD p.Ala239=](/variant/sgcd-p-ala239), [SGCD p.Ala239Thr](/variant/sgcd-p-ala239thr), [SGCD p.Arg165Ter](/variant/sgcd-p-arg165ter), [SGCD p.Arg97Ter](/variant/sgcd-p-arg97ter), [SGCD p.Arg31Trp](/variant/sgcd-p-arg31trp), [SGCD p.Ile64Thr](/variant/sgcd-p-ile64thr), [SGCD c.192+1G>A](/variant/sgcd-c-192-plus-1g-a), [SGCD c.294+1G>A](/variant/sgcd-c-294-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 352336). 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.*