Is DYSF p.Arg1173Cys (c.3517C>T) pathogenic?

DYSF p.Arg1173Cys (c.3517C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.6806); Ultra-rare (popmax 0.0549%, sas); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg1173Cys (c.3517C>T) in the general population?

DYSF p.Arg1173Cys (c.3517C>T) is ultra-rare (popmax 0.0549%, sas) (gnomAD).

What do computational predictors say about DYSF p.Arg1173Cys (c.3517C>T)?

AlphaMissense predicts likely pathogenic (score 0.6806) — an in-silico prediction, not a clinical call.

DYSF p.Arg1173Cys

Q: What condition is associated with DYSF p.Arg1173Cys (c.3517C>T)?

DYSF p.Arg1173Cys (c.3517C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.3517C>T · rs372297758 · VCV1677047

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6806 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0549%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.6806	likely pathogenic
REVEL	0.743	pathogenic-leaning
SaProt	LLR -14.59	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	32.0	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 R1155C vs ClinVar R1173C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0549% South Asian · 50/91,080 alleles

Filtering AF 0.0427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0057% 92/1,614,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0549%	1,822
Middle Eastern	0.0495%	2,021
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00333%	30,005
European (non-Finnish)	0.00288%	34,706
East Asian	0.00223%	44,874
Finnishnot grpmax-eligible	0.00156%	64,038

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.Arg1173Cys
Coding: c.3517C>T
MANE Select: NM_001130987
dbSNP: rs372297758
Type: single nucleotide variant
Location: chr2:71590231 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1173: the c2 4 domain

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

Disease context

neuromuscular disease caused by qualitative or quantitative defects of dysferlin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYSF p.Arg1173= Likely benign ★ same residue
DYSF p.Arg1173fs Pathogenic/Likely pathogenic ★★ same residue
DYSF p.Arg1173His Uncertain significance ★ ⚠ 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+4A>G 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-arg1173cys (accessed [today's date]).

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