Is DYSF p.Pro1038= (c.3114G>A) pathogenic?

DYSF p.Pro1038= (c.3114G>A) is classified Likely benign in DYSF (ClinVar, Expert panel, 7 submitters; last evaluated 2026-01-23). Rare (popmax 0.178%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Pro1038= (c.3114G>A) in the general population?

DYSF p.Pro1038= (c.3114G>A) is rare (popmax 0.178%, sas) (gnomAD).

DYSF p.Pro1038=

Q: What condition is associated with DYSF p.Pro1038= (c.3114G>A)?

DYSF p.Pro1038= (c.3114G>A) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.3114G>A · rs398123778 · VCV94299

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.178%, sas)

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

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

BS1

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.3060G>A p.(Pro1020=) variant in DYSF, which is also known as NM_001130987.2: c.3114G>A p.(Pro1038=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). This variant was detected in a heterozygous state in one individual with suspected LGMD and disease range dysferlin expression. This individual also had two additional variants in DYSF in unknown phase (PM3 and BP2 not met; PMID: 30564623, LOVD Individual #00222264; Jain Foundation Dysferlin Registry internal data communication). The filtering allele frequency for this variant is 0.001555 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 162/91072 South Asian chromosomes), which is higher than the VCEP threshold of 0.001 (BS1). The SpliceAI prediction score for this variant is 0.17, which is greater than the VCEP threshold of <0.05 (BP4 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 01/23/2026): BS1.

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

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 -2.3	GERP -4.3
Overall
CADD	14.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.178% South Asian · 162/91,072 alleles

Filtering AF 0.156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0175% 282/1,614,028 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.178%	562
Middle Eastern	0.0165%	6,060
African / African-American	0.0107%	9,379
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)	0.00873%	11,456
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,012

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.Pro1038=
Coding: c.3114G>A
MANE Select: NM_001130987
dbSNP: rs398123778
Type: single nucleotide variant
Location: chr2:71570627 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1038: a β-strand; a UniProt-annotated variant site (in lgmdr2)

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 neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Pro1038Gln Uncertain significance ★ ⚠ same residue
DYSF p.Pro1038Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Pro1038fs 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.1033+5G>A 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-pro1038 (accessed [today's date]).

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