Is AGRN p.Ser194fs (c.574_578dup) pathogenic?

AGRN p.Ser194fs (c.574578dup) is classified Pathogenic/Likely pathogenic in AGRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-02). Very rare (popmax 0.00244%, eas); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Ser194fs (c.574_578dup)?

AGRN p.Ser194fs (c.574_578dup) is associated with congenital myasthenic syndrome 8, congenital myasthenic syndrome (ClinVar).

How common is AGRN p.Ser194fs (c.574_578dup) in the general population?

AGRN p.Ser194fs (c.574_578dup) is very rare (popmax 0.00244%, eas) (gnomAD).

AGRN p.Ser194fs

c.574_578dup · rs1570190059 · VCV666960

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.45	GERP -2

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00244% East Asian · 1/40,982 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000287% 4/1,395,178 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00244%	40,982
Admixed American	0.00195%	51,190
European (non-Finnish)	0.000174%	573,579

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: AGRN
Protein: p.Ser194fs
Coding: c.574_578dup
MANE Select: NM_198576
dbSNP: rs1570190059
Type: Microsatellite
Location: chr1:1040717 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.79 · 1 PDB
Residue 194: the kazal-like 1 domain

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

Disease context

congenital myasthenic syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome

Similar variants

AGRN c.952+1_952+3del Likely pathogenic ★ same condition
AGRN p.Val369fs Pathogenic ★ same condition
AGRN c.4298+55_4298+56insGGGGGGGAGGGGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGG Uncertain significance ★ same condition
AGRN p.Ala1779dup Uncertain significance ★ same condition
AGRN p.Glu915_Ser916insGlu Uncertain significance ★ same condition
AGRN p.Lys199del Conflicting classifications of pathogenicity ★ same condition
AGRN p.Val19del Uncertain significance ★ same condition
AGRN c.4298+21_4298+22insGGGGAGGGGGGG Likely benign ★ 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/agrn-p-ser194fs (accessed [today's date]).

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