Is DYSF p.Leu1998Val (c.5992C>G) pathogenic?

DYSF p.Leu1998Val (c.5992C>G) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.3566); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DYSF p.Leu1998Val (c.5992C>G)?

DYSF p.Leu1998Val (c.5992C>G) is associated with Inborn genetic diseases, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

How common is DYSF p.Leu1998Val (c.5992C>G) in the general population?

DYSF p.Leu1998Val (c.5992C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYSF p.Leu1998Val (c.5992C>G)?

AlphaMissense predicts ambiguous (score 0.3566) — an in-silico prediction, not a clinical call.

DYSF p.Leu1998Val

c.5992C>G · rs746241195 · VCV856969

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3566 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3566	ambiguous
REVEL	0.662	pathogenic-leaning
SaProt	LLR -9.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	24.1	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 L1959V vs ClinVar L1998V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYSF
Protein: p.Leu1998Val
Coding: c.5992C>G
MANE Select: NM_001130987
dbSNP: rs746241195
Type: single nucleotide variant
Location: chr2:71679164 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1998: the 'disordered' region; a β-strand

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: neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Leu1998Pro Likely 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.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>A Pathogenic ★★★ same condition
DYSF c.1276+5G>C 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-leu1998val (accessed [today's date]).

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