Is DYSF p.Pro1753Ser (c.5257C>T) pathogenic?

DYSF p.Pro1753Ser (c.5257C>T) is classified Uncertain significance in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.6061); Ultra-rare (popmax 0.0198%, sas); Associated with Inborn genetic diseases.

What condition is associated with DYSF p.Pro1753Ser (c.5257C>T)?

DYSF p.Pro1753Ser (c.5257C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DYSF p.Pro1753Ser (c.5257C>T) in the general population?

DYSF p.Pro1753Ser (c.5257C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about DYSF p.Pro1753Ser (c.5257C>T)?

AlphaMissense predicts likely pathogenic (score 0.6061) — an in-silico prediction, not a clinical call.

DYSF p.Pro1753Ser

c.5257C>T · VCV3506191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6061	likely pathogenic
REVEL	0.688	pathogenic-leaning
SaProt	LLR -14.34	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, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	22.9	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 P1714S vs ClinVar P1753S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0198% South Asian · 18/91,082 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00118% 19/1,614,170 alleles · ultra-rare exomes 19/1,461,878 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
European (non-Finnish)	8.47e-05%	1,180,036

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.Pro1753Ser
Coding: c.5257C>T
MANE Select: NM_001130987
Type: single nucleotide variant
Location: chr2:71665244 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1714 UniProt numbering: an α-helix

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

Similar variants

DYSF p.Pro1753= Likely benign ★ same residue
DYSF p.Ala1024Pro Uncertain significance ★★ ⚠ same condition
DYSF p.Ala736Thr Uncertain significance ★★ ⚠ same condition
DYSF p.Ala829Val Uncertain significance ★★ ⚠ same condition
DYSF p.Arg1062His Uncertain significance ★★ ⚠ same condition
DYSF p.Arg1102Leu Uncertain significance ★★ same condition
DYSF p.Arg1111Cys Uncertain significance ★★ ⚠ same condition
DYSF p.Arg1169His Uncertain significance ★★ ⚠ 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-pro1753ser (accessed [today's date]).

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