Is DYSF p.Pro1418= (c.4254C>A) pathogenic?

DYSF p.Pro1418= (c.4254C>A) is classified Likely benign in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). Very rare (popmax 0.00833%, amr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Pro1418= (c.4254C>A) in the general population?

DYSF p.Pro1418= (c.4254C>A) is very rare (popmax 0.00833%, amr) (gnomAD).

DYSF p.Pro1418=

Q: What condition is associated with DYSF p.Pro1418= (c.4254C>A)?

DYSF p.Pro1418= (c.4254C>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.4254C>A · rs142769942 · VCV1149542

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.86	GERP -0.12, phastCons 0.003
Overall
CADD	1.093	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,006 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00112% 18/1,614,062 alleles · very rare exomes 12/1,461,854 · genomes 6/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,001
East Asian	0.00446%	22,441
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000763%	131,115

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.Pro1418=
Coding: c.4254C>A
MANE Select: NM_001130987
dbSNP: rs142769942
Type: single nucleotide variant
Location: chr2:71612673 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1418: a β-strand; the c2 5 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.Pro1418His Uncertain significance ★★ ⚠ same residue
DYSF p.Pro1418Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Pro1418Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Pro1418Ser Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro1418 (accessed [today's date]).

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