Is DYSF p.Ala1715Ser (c.5143G>T) pathogenic?

DYSF p.Ala1715Ser (c.5143G>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1231); Ultra-rare (popmax 0.0468%, eas); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

What condition is associated with DYSF p.Ala1715Ser (c.5143G>T)?

DYSF p.Ala1715Ser (c.5143G>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B, Miyoshi muscular dystrophy 1 (ClinVar).

How common is DYSF p.Ala1715Ser (c.5143G>T) in the general population?

DYSF p.Ala1715Ser (c.5143G>T) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about DYSF p.Ala1715Ser (c.5143G>T)?

AlphaMissense predicts likely benign (score 0.1231) — an in-silico prediction, not a clinical call.

DYSF p.Ala1715Ser

c.5143G>T · rs141137410 · VCV288630

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1231 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.1231	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -4.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.86, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	25.1	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 A1676S vs ClinVar A1715S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% East Asian · 21/44,878 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.0411% 663/1,614,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.417%	240
Remaining individualsnot grpmax-eligible	0.0736%	1,359
East Asiangrpmax	0.0468%	2,137
South Asian	0.0307%	3,253
European (non-Finnish)	0.0253%	3,960
African / African-American	0.004%	25,019

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1715Ser
Coding: c.5143G>T
MANE Select: NM_001130987
dbSNP: rs141137410
Type: single nucleotide variant
Location: chr2:71664407 (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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Ala1715Asp 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+1G>C 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-ala1715ser (accessed [today's date]).

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