Is AGRN p.Val369fs (c.1105_1106del) pathogenic?

AGRN p.Val369fs (c.11051106del) is classified Pathogenic in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-13). Very rare (popmax 0.00017%, nfe); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Val369fs (c.1105_1106del)?

AGRN p.Val369fs (c.1105_1106del) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Val369fs (c.1105_1106del) in the general population?

AGRN p.Val369fs (c.1105_1106del) is very rare (popmax 0.00017%, nfe) (gnomAD).

AGRN p.Val369fs

c.1105_1106del · rs2100635414 · VCV1384683

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

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 6 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.2	GERP -1.1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,248 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,459,250 alleles · very rare

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.Val369fs
Coding: c.1105_1106del
MANE Select: NM_198576
dbSNP: rs2100635414
Type: Microsatellite
Location: chr1:1041627 (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 369: a disulfide bond; the kazal-like 3 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

Similar variants

AGRN p.Val369= Likely benign ★★ same residue
AGRN p.Val369Ile Uncertain significance ★ same residue
AGRN p.Ser194fs Pathogenic/Likely pathogenic ★★ same condition
AGRN c.952+1_952+3del Likely 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

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-val369fs (accessed [today's date]).

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