Is DYSF p.Pro1830Ser (c.5488C>T) pathogenic?

DYSF p.Pro1830Ser (c.5488C>T) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-02-09). AlphaMissense: likely pathogenic (0.6918); Ultra-rare (popmax 0.0516%, amr); Associated with Inborn genetic diseases.

How common is DYSF p.Pro1830Ser (c.5488C>T) in the general population?

DYSF p.Pro1830Ser (c.5488C>T) is ultra-rare (popmax 0.0516%, amr) (gnomAD).

What do computational predictors say about DYSF p.Pro1830Ser (c.5488C>T)?

AlphaMissense predicts likely pathogenic (score 0.6918) — an in-silico prediction, not a clinical call.

DYSF p.Pro1830Ser

Q: What condition is associated with DYSF p.Pro1830Ser (c.5488C>T)?

DYSF p.Pro1830Ser (c.5488C>T) is associated with Inborn genetic diseases, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.5488C>T · rs145832952 · VCV69635

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.6918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6918	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -10.98	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 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	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1791S vs ClinVar P1830S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% Admixed American · 31/60,022 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0191% 309/1,613,958 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0516%	1,936
European (non-Finnish)	0.0225%	4,436
Remaining individualsnot grpmax-eligible	0.0176%	5,682
African / African-American	0.00133%	75,062

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.Pro1830Ser
Coding: c.5488C>T
MANE Select: NM_001130987
dbSNP: rs145832952
Type: single nucleotide variant
Location: chr2:71668784 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1830: the c2 7 domain

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

Disease context

Inborn genetic diseases — 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.Pro1830= 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-pro1830ser (accessed [today's date]).

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