# NM_001130987.2(DYSF):c.3114G>A (p.Pro1038=)

https://sugi.bio/variant/dysf-p-pro1038

## Summary

**DYSF p.Pro1038= (c.3114G>A)** is classified **Likely benign** in DYSF (ClinVar, Expert panel, 7 submitters; last evaluated 2026-01-23). Rare (popmax 0.178%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Likely benign · review: Expert panel · rsID rs398123778 · 7 submitters · 3 linked conditions · rare (popmax 0.178%, sas)

## For patients & families {#patients}

This is a change in the DYSF gene that is classified as likely benign — not considered disease-causing, submitted by 7 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 | [DYSF](https://sugi.bio/atlas/gene/DYSF/) |
| Protein change (HGVS p.) | p.Pro1038= |
| Coding change (HGVS c.) | c.3114G>A |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs398123778](https://www.ncbi.nlm.nih.gov/snp/rs398123778/) |
| Variant type | single nucleotide variant |
| Location | chr2:71570627-71570627 (GRCh38) |
| ClinVar | [VCV94299](https://www.ncbi.nlm.nih.gov/clinvar/variation/94299/) |

**All HGVS expressions:** `LRG_845:g.122005G>A`, `LRG_845t1:c.3060G>A`, `LRG_845t2:c.3114G>A`, `NC_000002.11:g.71797757G>A`, `NC_000002.12:g.71570627G>A`, `NG_008694.1:g.122005G>A`, `NM_001130455.2:c.3063G>A`, `NM_001130976.2:c.3018G>A`, `NM_001130977.2:c.3018G>A`, `NM_001130978.2:c.3060G>A`, `NM_001130979.2:c.3153G>A`, `NM_001130980.2:c.3111G>A`, `NM_001130981.2:c.3111G>A`, `NM_001130982.2:c.3156G>A`, `NM_001130983.2:c.3063G>A`, `NM_001130984.2:c.3021G>A`, `NM_001130985.2:c.3114G>A`, `NM_001130986.2:c.3021G>A`, `NM_001130987.2:c.3114G>A`, `NM_003494.4:c.3060G>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 (below), not from a missing predictor score.
- Conservation: phyloP -2.32, GERP -4.27 — fast-evolving / accelerated position
- CADD: **PHRED 14.36**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.178%** (sas) · FAF95 0.156% · FAF99 0.147% · 162/91,072 in the highest group · 282/1,614,028 alleles overall — rare (popmax 0.178%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.178% | 562 |
| Middle Eastern | 0.0165% | 6,060 |
| African / African-American | 0.0107% | 9,379 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,415 |
| European (non-Finnish) | 0.00873% | 11,456 |
| East Asian | 0.00223% | 44,878 |
| Admixed American | 0.00167% | 60,012 |

*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 **1038** lies in a β-strand; a UniProt-annotated variant site (in lgmdr2).

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.


### 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}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-01-23.

**Submitter consensus:** conflicting (4 Likely benign, 2 Uncertain significance, 1 Likely Benign).

**Submission history:** 7 submissions (2013–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Limb Girdle Muscular Dystrophy VCEP (autosomal recessive limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`.
*Considered but not met:* `PM3`, `BP7`, `BP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_003494.4: c.3060G>A p.(Pro1020=) variant in DYSF, which is also known as NM_001130987.2: c.3114G>A p.(Pro1038=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). This variant was detected in a heterozygous state in one individual with suspected LGMD and disease range dysferlin expression. This individual also had two additional variants in DYSF in unknown phase (PM3 and BP2 not met; PMID: 30564623, LOVD Individual #00222264; Jain Foundation Dysferlin Registry internal data communication). The filtering allele frequency for this variant is 0.001555 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 162/91072 South Asian chromosomes), which is higher than the VCEP threshold of 0.001 (BS1). The SpliceAI prediction score for this variant is 0.17, which is greater than the VCEP threshold of <0.05 (BP4 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 01/23/2026): BS1.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2026-01-23 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/9e5bf7d2-f973-4ada-b086-7cb8c9e3f36a).*
*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 |
| --- | --- | --- | --- | --- |
| Counsyl | Likely benign | no assertion criteria provided | clinical testing | 2017-04-04 |
| 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 | 2020-09-16 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-05-28 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Likely Benign | reviewed by expert panel | curation | 2026-01-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-29 |

## 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 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):** Autosomal recessive limb-girdle muscular dystrophy, not provided, Autosomal recessive limb-girdle muscular dystrophy type 2B, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, not specified, AllHighlyPenetrant, Dysferlinopathy, Qualitative or quantitative defects of dysferlin, none provided, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3.

## Same-residue context {#hotspot}

Residue **1038** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYSF p.Pro1038fs](/variant/dysf-p-pro1038fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Pro1038Gln](/variant/dysf-p-pro1038gln), [DYSF p.Pro1038Leu](/variant/dysf-p-pro1038leu), [DYSF p.Pro1038fs](/variant/dysf-p-pro1038fs), [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.1033+5G>A](/variant/dysf-c-1033-plus-5g-a), [DYSF c.1149+1G>A](/variant/dysf-c-1149-plus-1g-a).

### 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 94299). 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.*