Is DYSF p.Arg334Trp (c.1000C>T) pathogenic?

DYSF p.Arg334Trp (c.1000C>T) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-17). AlphaMissense: ambiguous (0.3934); Very rare (popmax 0.00667%, afr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg334Trp (c.1000C>T) in the general population?

DYSF p.Arg334Trp (c.1000C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about DYSF p.Arg334Trp (c.1000C>T)?

AlphaMissense predicts ambiguous (score 0.3934) — an in-silico prediction, not a clinical call.

DYSF p.Arg334Trp

Q: What condition is associated with DYSF p.Arg334Trp (c.1000C>T)?

DYSF p.Arg334Trp (c.1000C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1000C>T · rs184771575 · VCV1360207

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.3934	ambiguous
REVEL	0.591	indeterminate
SaProt	LLR -8.27	tolerated
Splicing
SpliceAI	Δ0.21	donor loss · deltas
Pangolin	Δ0.30	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · 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 R302W vs ClinVar R334W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,998 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0026% 42/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	15,000
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.00288%	34,703
South Asian	0.0011%	91,078

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.Arg334Trp
Coding: c.1000C>T
MANE Select: NM_001130987
dbSNP: rs184771575
Type: single nucleotide variant
Location: chr2:71517037 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

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.Arg334= Uncertain significance ★ same residue
DYSF p.Arg334Gln 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
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-arg334trp (accessed [today's date]).

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