# NM_001130987.2(DYSF):c.5138T>C (p.Phe1713Ser)

https://sugi.bio/variant/dysf-p-phe1713ser

## Summary

**DYSF p.Phe1713Ser (c.5138T>C)** is classified **Uncertain significance** in DYSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-10-28). AlphaMissense: likely pathogenic (0.6424); Absent from gnomAD v4.1; Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs886044317 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DYSF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002003/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.Phe1713Ser |
| Coding change (HGVS c.) | c.5138T>C |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs886044317](https://www.ncbi.nlm.nih.gov/snp/rs886044317/) |
| Variant type | single nucleotide variant |
| Location | chr2:71664402-71664402 (GRCh38) |
| ClinVar | [VCV289960](https://www.ncbi.nlm.nih.gov/clinvar/variation/289960/) |

**All HGVS expressions:** `LRG_845:g.215780T>C`, `LRG_845t1:c.5021T>C`, `LRG_845t2:c.5138T>C`, `NC_000002.11:g.71891532T>C`, `NC_000002.12:g.71664402T>C`, `NG_008694.1:g.215780T>C`, `NM_001130455.2:c.5024T>C`, `NM_001130976.2:c.4979T>C`, `NM_001130977.2:c.5042T>C`, `NM_001130978.2:c.5084T>C`, `NM_001130979.2:c.5114T>C`, `NM_001130980.2:c.5072T>C`, `NM_001130981.2:c.5135T>C`, `NM_001130982.2:c.5117T>C`, `NM_001130983.2:c.5087T>C`, `NM_001130984.2:c.5045T>C`, `NM_001130985.2:c.5075T>C`, `NM_001130986.2:c.4982T>C`, `NM_001130987.2:c.5138T>C`, `NM_003494.4:c.5021T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6424)
- REVEL 0.571 (indeterminate)
- SaProt LLR -7.101 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.892, GERP 1.98, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **F1674S** vs ClinVar **F1713S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.4**. 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 0.97** across the covering region of the MANE Select transcript (71,569,910–71,686,489), spanning 116,579 bp. Chi-square p 0.28. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.88 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **1713** lies in an α-helix.

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2020-10-28.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2016–2020); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-08-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-10-28 |

## Associated conditions {#conditions}

[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):** Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, not provided, none provided, Qualitative or quantitative defects of dysferlin, Dysferlinopathy.

## Same-residue context {#hotspot}

Residue **1713** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYSF p.Phe1713fs](/variant/dysf-p-phe1713fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Phe1713Leu](/variant/dysf-p-phe1713leu), [DYSF p.Phe1713fs](/variant/dysf-p-phe1713fs), [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+4A>G](/variant/dysf-c-1149-plus-4a-g), [DYSF c.1276+5G>A](/variant/dysf-c-1276-plus-5g-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 289960). 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.*