Is DYSF p.Glu489Lys (c.1465G>A) pathogenic?

DYSF p.Glu489Lys (c.1465G>A) is classified Benign in DYSF (ClinVar, Expert panel, 15 submitters; last evaluated 2025-01-08). AlphaMissense: ambiguous (0.5242); Low-frequency (popmax 2.26%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Glu489Lys (c.1465G>A) in the general population?

DYSF p.Glu489Lys (c.1465G>A) is low-frequency (popmax 2.26%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Glu489Lys (c.1465G>A)?

AlphaMissense predicts ambiguous (score 0.5242) — an in-silico prediction, not a clinical call.

DYSF p.Glu489Lys

Q: What condition is associated with DYSF p.Glu489Lys (c.1465G>A)?

DYSF p.Glu489Lys (c.1465G>A) 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).

c.1465G>A · rs61740288 · VCV94270

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

AlphaMissense

ambiguous

0.5242 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.26%, nfe)

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):

BA1

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1369G>A variant in DYSF, which is also known as NM_001130987.2: c.1465G>A (p.Glu489Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 457 (p.Glu457Lys). The filtering allele frequency of the variant is 0.02368 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 4291/251472), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.28 and the computational predictor REVEL gives a score of 0.41. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). 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.

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

Computational evidence

Protein change
AlphaMissense	0.5242	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -9.13	tolerated
Splicing
SpliceAI	Δ0.28	acceptor loss, 15 bp away · masked 0 · deltas
Pangolin	Δ0.23	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	27.4	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 E457K vs ClinVar E489K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.26% European (non-Finnish) · 26,681/1,179,880 alleles

Filtering AF 2.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.23%

Overall 1.99% 32,136/1,613,910 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.99%	33
Finnishnot grpmax-eligible	2.49%	40
European (non-Finnish)grpmax	2.26%	44
Middle Eastern	2.01%	50
Remaining individualsnot grpmax-eligible	1.88%	53
Admixed American	1.11%	90
Amishnot grpmax-eligible	1.1%	91
South Asian	0.747%	134
African / African-American	0.392%	255
East Asian	0.0535%	1,870

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu489Lys
Coding: c.1465G>A
MANE Select: NM_001130987
dbSNP: rs61740288
Type: single nucleotide variant
Location: chr2:71535283 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 489: the c2 3 domain

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

Similar variants

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DYSF c.1033+5G>A Likely pathogenic ★★★ same condition
DYSF c.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+1G>C Pathogenic ★★★ same condition
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1149+5G>A Pathogenic ★★★ same condition

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-glu489lys (accessed [today's date]).

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