Is DYSF p.Pro2009Ser (c.6025C>T) pathogenic?

DYSF p.Pro2009Ser (c.6025C>T) is classified Pathogenic/Likely pathogenic in DYSF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.8426); Very rare (popmax 0.0011%, sas); Associated with Miyoshi muscular dystrophy 1.

What condition is associated with DYSF p.Pro2009Ser (c.6025C>T)?

DYSF p.Pro2009Ser (c.6025C>T) is associated with Miyoshi muscular dystrophy 1, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Pro2009Ser (c.6025C>T) in the general population?

DYSF p.Pro2009Ser (c.6025C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Miyoshi myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DYSF p.Pro2009Ser (c.6025C>T)?

AlphaMissense predicts likely pathogenic (score 0.8426) — an in-silico prediction, not a clinical call.

DYSF p.Pro2009Ser

c.6025C>T · rs1057521141 · VCV381677

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8426 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Miyoshi muscular dystrophy 1

Computational evidence

Protein change
AlphaMissense	0.8426	likely pathogenic ✓ concordant with ClinVar
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -15.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	25.1	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 P1970S vs ClinVar P2009S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,072 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000616% 9/1,461,782 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,249
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000508%	196,659

Remaining individuals 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.Pro2009Ser
Coding: c.6025C>T
MANE Select: NM_001130987
dbSNP: rs1057521141
Type: single nucleotide variant
Location: chr2:71679197 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 2009: the 'disordered' region

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

Disease context

Miyoshi muscular dystrophy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B distal myopathy with anterior tibial onset neuromuscular disease caused by qualitative or quantitative defects of dysferlin

For Miyoshi myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

DYSF p.Pro2009= Likely benign ★ same residue
DYSF c.1003-3C>A Pathogenic ★★★ same condition
DYSF c.1033+1G>A Pathogenic ★★★ same condition
DYSF c.1033+4A>T 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.1276+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-pro2009ser (accessed [today's date]).

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