# NM_001130987.2(DYSF):c.2554A>G (p.Ile852Val)

https://sugi.bio/variant/dysf-p-ile852val

## Summary

**DYSF p.Ile852Val (c.2554A>G)** is classified **Benign** in DYSF (ClinVar, Expert panel, 14 submitters; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0804); Common (popmax 8.67%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Benign · review: Expert panel · rsID rs34671418 · 14 submitters · 3 linked conditions · AlphaMissense likely benign · common (popmax 8.67%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DYSF gene that is classified as benign — not considered disease-causing, submitted by 14 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.Ile852Val |
| Coding change (HGVS c.) | c.2554A>G |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs34671418](https://www.ncbi.nlm.nih.gov/snp/rs34671418/) |
| Variant type | single nucleotide variant |
| Location | chr2:71564202-71564202 (GRCh38) |
| ClinVar | [VCV94289](https://www.ncbi.nlm.nih.gov/clinvar/variation/94289/) |

**All HGVS expressions:** `LRG_845:g.115580A>G`, `LRG_845t1:c.2500A>G`, `LRG_845t2:c.2554A>G`, `NC_000002.11:g.71791332A>G`, `NC_000002.12:g.71564202A>G`, `NG_008694.1:g.115580A>G`, `NM_001130455.2:c.2503A>G`, `NM_001130976.2:c.2458A>G`, `NM_001130977.2:c.2458A>G`, `NM_001130978.2:c.2500A>G`, `NM_001130979.2:c.2593A>G`, `NM_001130980.2:c.2551A>G`, `NM_001130981.2:c.2551A>G`, `NM_001130982.2:c.2596A>G`, `NM_001130983.2:c.2503A>G`, `NM_001130984.2:c.2461A>G`, `NM_001130985.2:c.2554A>G`, `NM_001130986.2:c.2461A>G`, `NM_001130987.2:c.2554A>G`, `NM_003494.4:c.2500A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 8.67%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0804)
- REVEL 0.077 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.876 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.465, GERP 2.09, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **I834V** vs ClinVar **I852V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 21.7**. 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 0.82** across the covering region of the MANE Select transcript (71,551,716–71,569,909), spanning 18,193 bp. Chi-square p 4.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **8.67%** (afr) · FAF95 8.5% · FAF99 8.43% · 6,508/75,034 in the highest group · 41,481/1,614,180 alleles overall — common (popmax 8.67%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 8.67% | 12 |
| Finnish (not grpmax-eligible) | 3.31% | 30 |
| Ashkenazi Jewish (not grpmax-eligible) | 2.56% | 39 |
| European (non-Finnish) | 2.52% | 40 |
| Remaining individuals (not grpmax-eligible) | 2.36% | 42 |
| Admixed American | 1.26% | 79 |
| Middle Eastern | 0.907% | 110 |
| South Asian | 0.0417% | 2,397 |

*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 **852** lies in a β-strand.

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}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-08.

**Submitter consensus:** conflicting (8 Benign, 5 Likely benign, 1 benign).

**Submission history:** 14 submissions (2012–2026); classifications have differed over time.

**ClinGen expert panel:** 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):** `BP4`, `BA1`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_003494.4: c.2500A>G variant in DYSF, which is also known as NM_001130987.2: c.2554A>G p.(Ile852Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 834 (p.Ile834Val). The filtering allele frequency of the variant is 0.08367 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1541/31380), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0, which suggests it does not impact splicing and is below the LGMD VCEP threshold of ≤0.05. The computational predictor REVEL gives a score of 0.08, which is below the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1) (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP4.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-01-08 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/e670c716-71d2-4c5a-9f1c-dec8f61eb22b).*
*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 |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2017-12-06 |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Benign | reviewed by expert panel | curation | 2025-01-08 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2012-07-12 |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2025-02-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-12 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-02-02 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## 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 specified, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Autosomal recessive limb-girdle muscular dystrophy type 2B, not provided, AllHighlyPenetrant, Dysferlinopathy, Qualitative or quantitative defects of dysferlin, none provided, 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.1033+5G>A](/variant/dysf-c-1033-plus-5g-a), [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.1149+5G>A](/variant/dysf-c-1149-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 94289). 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.*