Is AGRN p.Arg524Trp (c.1570C>T) pathogenic?

AGRN p.Arg524Trp (c.1570C>T) is classified Conflicting classifications of pathogenicity in AGRN (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). Rare (popmax 0.367%, afr); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Arg524Trp (c.1570C>T)?

AGRN p.Arg524Trp (c.1570C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Arg524Trp (c.1570C>T) in the general population?

AGRN p.Arg524Trp (c.1570C>T) is rare (popmax 0.367%, afr) (gnomAD).

AGRN p.Arg524Trp

c.1570C>T · rs144164397 · VCV446814

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.367%, afr)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.213	benign-leaning
Splicing
SpliceAI	Δ0.32	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP 0.16, phastCons 0.47
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.367% African / African-American · 275/74,922 alleles

Filtering AF 0.331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.318%

Overall 0.0225% 362/1,607,190 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.367%	272
Admixed American	0.0354%	2,822
Remaining individualsnot grpmax-eligible	0.0321%	3,115
East Asian	0.00448%	22,337
South Asian	0.00441%	22,651
European (non-Finnish)	0.00339%	29,457

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.Arg524Trp
Coding: c.1570C>T
MANE Select: NM_198576
dbSNP: rs144164397
Type: single nucleotide variant
Location: chr1:1043424 (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 524: the kazal-like 5 domain; a disulfide bond

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.Arg524Gln Uncertain significance ★ same residue
AGRN c.3632-1G>C Likely pathogenic ★★ same condition
AGRN p.Arg1671Ter Pathogenic/Likely pathogenic ★★ same condition
AGRN p.Arg834Ter Pathogenic/Likely pathogenic ★★ same condition
AGRN p.Gly1582Arg Pathogenic ★★ same condition
AGRN p.Gly1675Ser Pathogenic/Likely pathogenic ★★ same condition
AGRN c.1177+4A>G Uncertain significance ★★ same condition
AGRN c.1384+6C>T Uncertain significance ★★ 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-arg524trp (accessed [today's date]).

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