# NM_001130987.2(DYSF):c.1149T>G (p.Pro383=)

https://sugi.bio/variant/dysf-p-pro383

## Summary

**DYSF p.Pro383= (c.1149T>G)** is classified **Conflicting classifications of pathogenicity** in DYSF (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-31). Rare (popmax 0.225%, eas); Associated with Miyoshi muscular dystrophy 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs199955501 · 9 submitters · 3 linked conditions · rare (popmax 0.225%, eas)

## For patients & families {#patients}

This is a change in the DYSF gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to Miyoshi muscular dystrophy 1.

*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) | Adult |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Diagnostic panels | DYSF is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Miyoshi myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gait disturbance — Frequent (79-30%)
- Shoulder girdle muscle weakness — Frequent (79-30%)
- Difficulty climbing stairs — Frequent (79-30%)
- Difficulty standing — Frequent (79-30%)
- Quadriceps muscle weakness — Frequent (79-30%)
- Exercise-induced myalgia — Frequent (79-30%)
- Pelvic girdle muscle weakness — Frequent (79-30%)
- Proximal amyotrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025425/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYSF](https://sugi.bio/atlas/gene/DYSF/) |
| Protein change (HGVS p.) | p.Pro383= |
| Coding change (HGVS c.) | c.1149T>G |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs199955501](https://www.ncbi.nlm.nih.gov/snp/rs199955501/) |
| Variant type | single nucleotide variant |
| Location | chr2:71520904-71520904 (GRCh38) |
| ClinVar | [VCV288411](https://www.ncbi.nlm.nih.gov/clinvar/variation/288411/) |

**All HGVS expressions:** `LRG_845:g.72282T>G`, `LRG_845t1:c.1053T>G`, `LRG_845t2:c.1149T>G`, `NC_000002.11:g.71748034T>G`, `NC_000002.12:g.71520904T>G`, `NG_008694.1:g.72282T>G`, `NM_001130455.2:c.1056T>G`, `NM_001130976.2:c.1053T>G`, `NM_001130977.2:c.1053T>G`, `NM_001130978.2:c.1053T>G`, `NM_001130979.2:c.1146T>G`, `NM_001130980.2:c.1146T>G`, `NM_001130981.2:c.1146T>G`, `NM_001130982.2:c.1149T>G`, `NM_001130983.2:c.1056T>G`, `NM_001130984.2:c.1056T>G`, `NM_001130985.2:c.1149T>G`, `NM_001130986.2:c.1056T>G`, `NM_001130987.2:c.1149T>G`, `NM_003494.4:c.1053T>G`

## 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 0.28) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -12.689, GERP -4.48 — fast-evolving / accelerated position
- CADD: **PHRED 0.008**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.28**. Largest is donor gain at this position.
- 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 **0.225%** (eas) · FAF95 0.19% · FAF99 0.176% · 101/44,880 in the highest group · 107/1,613,932 alleles overall — rare (popmax 0.225%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.225% | 444 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,623 |
| South Asian | 0.0011% | 91,080 |
| European (non-Finnish) | 8.48e-05% | 1,179,857 |

*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}

**DYSF** population constraint: LOEUF 0.836, pLI 3.6575e-52, missense-Z 1.3979. *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 **383** lies in a β-strand; the c2 3 domain.

AlphaFold model confidence (whole protein): pLDDT 79.25, 28% of residues very-high.

**11 experimental structure(s)** (PDB): [4CAH](https://www.rcsb.org/structure/4CAH), [4CAI](https://www.rcsb.org/structure/4CAI), [4IHB](https://www.rcsb.org/structure/4IHB), [4IQH](https://www.rcsb.org/structure/4IQH), [7JOF](https://www.rcsb.org/structure/7JOF), [7K6B](https://www.rcsb.org/structure/7K6B) — incl. mutant structure 4IQH.

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

*Describes the biological roles of DYSF (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.*

**How this variant is thought to act:** DYSF's established molecular role includes calcium ion binding. p.Pro383= falls in the c2 3 domain.


### Pathways affected {#pathways}

DYSF participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** calcium ion binding, phospholipid binding, calcium-dependent phospholipid binding.

**Biological process:** monocyte activation involved in immune response, macrophage activation involved in immune response, negative regulation of phagocytosis.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-31.

**Submitter consensus:** conflicting (5 Likely benign, 3 Uncertain significance, 1 benign).

**Submission history:** 9 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2024-04-05 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-01-20 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-18 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-01-23 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-10-26 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-06-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-31 |

## Associated conditions {#conditions}

[Miyoshi muscular dystrophy 1](https://sugi.bio/atlas/disease/miyoshi-muscular-dystrophy-1/), [autosomal recessive limb-girdle muscular dystrophy type 2B](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2b/), [neuromuscular disease caused by qualitative or quantitative defects of dysferlin](https://sugi.bio/atlas/disease/neuromuscular-disease-caused-by-qualitative-or-quantitative-defects-of-dysferlin/).

**Reported phenotype names (ClinVar):** Miyoshi muscular dystrophy 1, not specified, Autosomal recessive limb-girdle muscular dystrophy type 2B, not provided, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, DYSF-related disorder, DYSF-related condition, DYSF-related disorders, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, Limb-girdle muscular dystrophy, type 2B.

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF c.1003-3C>A](/variant/dysf-c-1003-minus-3c-a), [DYSF c.1033+1G>A](/variant/dysf-c-1033-plus-1g-a), [DYSF c.1033+4A>T](/variant/dysf-c-1033-plus-4a-t), [DYSF c.1149+1G>A](/variant/dysf-c-1149-plus-1g-a), [DYSF c.1149+1G>C](/variant/dysf-c-1149-plus-1g-c), [DYSF c.1149+4A>G](/variant/dysf-c-1149-plus-4a-g), [DYSF c.1276+5G>A](/variant/dysf-c-1276-plus-5g-a), [DYSF c.1276+5G>C](/variant/dysf-c-1276-plus-5g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 288411). 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.*