Is DYSF p.Ile852Val (c.2554A>G) pathogenic?

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.

What do computational predictors say about DYSF p.Ile852Val (c.2554A>G)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

DYSF p.Ile852Val

Q: What condition is associated with DYSF p.Ile852Val (c.2554A>G)?

DYSF p.Ile852Val (c.2554A>G) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

Q: How common is DYSF p.Ile852Val (c.2554A>G) in the general population?

DYSF p.Ile852Val (c.2554A>G) is common (popmax 8.67%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2554A>G · rs34671418 · VCV94289

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.67%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Benign for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

BP4 BA1

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.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I834V vs ClinVar I852V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.67% African / African-American · 6,508/75,034 alleles

Filtering AF 8.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.43%

Overall 2.57% 41,481/1,614,180 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.67%	12
Finnishnot grpmax-eligible	3.31%	30
Ashkenazi Jewishnot grpmax-eligible	2.56%	39
European (non-Finnish)	2.52%	40
Remaining individualsnot grpmax-eligible	2.36%	42
Admixed American	1.26%	79
Middle Eastern	0.907%	110
South Asian	0.0417%	2,397

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DYSF
Protein: p.Ile852Val
Coding: c.2554A>G
MANE Select: NM_001130987
dbSNP: rs34671418
Type: single nucleotide variant
Location: chr2:71564202 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 852: a β-strand

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin

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Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dysf-p-ile852val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown