Is AGRN p.Ala519Ser (c.1555G>T) pathogenic?

AGRN p.Ala519Ser (c.1555G>T) is classified Uncertain significance in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). Very rare (popmax 0.00441%, sas); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Ala519Ser (c.1555G>T)?

AGRN p.Ala519Ser (c.1555G>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Ala519Ser (c.1555G>T) in the general population?

AGRN p.Ala519Ser (c.1555G>T) is very rare (popmax 0.00441%, sas) (gnomAD).

AGRN p.Ala519Ser

c.1555G>T · VCV3341337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00441%, sas)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.153	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00441% South Asian · 4/90,614 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000895%

Overall 0.000311% 5/1,608,630 alleles · very rare exomes 5/1,456,320 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00441%	22,653
Remaining individualsnot grpmax-eligible	0.0016%	62,310

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.Ala519Ser
Coding: c.1555G>T
MANE Select: NM_198576
Type: single nucleotide variant
Location: chr1:1043409 (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 519: the kazal-like 5 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.Ala519= Likely benign ★★ 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-ala519ser (accessed [today's date]).

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