Is DYSF p.Ile1316Val (c.3946A>G) pathogenic?

DYSF p.Ile1316Val (c.3946A>G) is classified Benign in DYSF (ClinVar, Expert panel, 18 submitters; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0749); Rare (popmax 0.757%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Ile1316Val (c.3946A>G)?

DYSF p.Ile1316Val (c.3946A>G) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Ile1316Val (c.3946A>G) in the general population?

DYSF p.Ile1316Val (c.3946A>G) is rare (popmax 0.757%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Ile1316Val (c.3946A>G)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

DYSF p.Ile1316Val

c.3946A>G · rs121908954 · VCV6667

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.757%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Benign for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.3892A>G variant in DYSF, which is also known as NM_001130987.2: c.3946A>G p.(Ile1316Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1298 (p.Ile1298Val). The filtering allele frequency of the variant is 0.006916 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 695/152140), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.12 and the computational predictor REVEL gives a score of 0.42. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.415	indeterminate
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	24.2	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 I1298V vs ClinVar I1316V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.757% European (non-Finnish) · 8,936/1,179,912 alleles

Filtering AF 0.744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.739%

Overall 0.624% 10,072/1,613,374 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.757%	132
Finnishnot grpmax-eligible	0.608%	164
Remaining individualsnot grpmax-eligible	0.498%	201
Admixed American	0.265%	377
Ashkenazi Jewishnot grpmax-eligible	0.149%	672
South Asian	0.144%	694
Middle Eastern	0.132%	757
African / African-American	0.127%	790
East Asian	0.00223%	44,866

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.Ile1316Val
Coding: c.3946A>G
MANE Select: NM_001130987
dbSNP: rs121908954
Type: single nucleotide variant
Location: chr2:71602794 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1316: the c2 5 domain

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

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B distal myopathy with anterior tibial onset neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Ile1316= 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.1033+5G>A 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

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-ile1316val (accessed [today's date]).

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