Is DYSF p.Arg1114His (c.3341G>A) pathogenic?

DYSF p.Arg1114His (c.3341G>A) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.2955); Low-frequency (popmax 1.99%, afr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg1114His (c.3341G>A) in the general population?

DYSF p.Arg1114His (c.3341G>A) is low-frequency (popmax 1.99%, afr) (gnomAD).

What do computational predictors say about DYSF p.Arg1114His (c.3341G>A)?

AlphaMissense predicts likely benign (score 0.2955) — an in-silico prediction, not a clinical call.

DYSF p.Arg1114His

Q: What condition is associated with DYSF p.Arg1114His (c.3341G>A)?

DYSF p.Arg1114His (c.3341G>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.3341G>A · rs59915619 · VCV128947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2955 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.99%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.2955	likely benign
REVEL	0.618	indeterminate
SaProt	LLR -7.87	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	31.0	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 R1096H vs ClinVar R1114H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.99% African / African-American · 1,492/75,068 alleles

Filtering AF 1.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.87%

Overall 0.103% 1,659/1,614,092 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.99%	50
Remaining individualsnot grpmax-eligible	0.106%	947
Middle Eastern	0.099%	1,010
Admixed American	0.09%	1,112
Finnishnot grpmax-eligible	0.0235%	4,264
East Asian	0.00223%	44,882
South Asian	0.0022%	45,537
European (non-Finnish)	0.00195%	51,304

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.Arg1114His
Coding: c.3341G>A
MANE Select: NM_001130987
dbSNP: rs59915619
Type: single nucleotide variant
Location: chr2:71574310 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1114: a turn

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

Similar variants

DYSF p.Arg1114Cys Uncertain significance ★ ⚠ same residue
DYSF p.Arg1114= Likely benign ★ same residue
DYSF p.Arg1114Leu Uncertain significance ⚠ same residue
DYSF p.Arg1114Ser 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

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-arg1114his (accessed [today's date]).

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