Is DYSF p.Arg1853Cys (c.5557C>T) pathogenic?

DYSF p.Arg1853Cys (c.5557C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.7739); Very rare (popmax 0.00227%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Arg1853Cys (c.5557C>T) in the general population?

DYSF p.Arg1853Cys (c.5557C>T) is very rare (popmax 0.00227%, sas) (gnomAD).

What do computational predictors say about DYSF p.Arg1853Cys (c.5557C>T)?

AlphaMissense predicts likely pathogenic (score 0.7739) — an in-silico prediction, not a clinical call.

DYSF p.Arg1853Cys

Q: What condition is associated with DYSF p.Arg1853Cys (c.5557C>T)?

DYSF p.Arg1853Cys (c.5557C>T) 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.5557C>T · rs1280185461 · VCV557327

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.7739	likely pathogenic
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -15.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.23	acceptor loss, 10 bp away · masked 0 · deltas
Pangolin	Δ0.25	loss · gain 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	26.8	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 R1814C vs ClinVar R1853C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% South Asian · 2/88,296 alleles

Filtering AF 0.000376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000141%

Overall 0.000562% 9/1,601,670 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00322%	31,055
South Asiangrpmax	0.00227%	44,148
Admixed American	0.00172%	58,236
African / African-American	0.00134%	74,802
European (non-Finnish)	0.000256%	391,325

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.Arg1853Cys
Coding: c.5557C>T
MANE Select: NM_001130987
dbSNP: rs1280185461
Type: single nucleotide variant
Location: chr2:71669122 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1853: the c2 7 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

DYSF p.Arg1853His Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Arg1853= Likely benign ★ same residue
DYSF p.Arg1853fs Pathogenic ★ 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.1033+5G>A Likely pathogenic ★★★ same condition
DYSF c.1149+1G>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-arg1853cys (accessed [today's date]).

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