Is AGRN p.Glu728Val (c.2183A>T) pathogenic?

AGRN p.Glu728Val (c.2183A>T) is classified Benign in AGRN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Low-frequency (popmax 4.27%, nfe); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Glu728Val (c.2183A>T)?

AGRN p.Glu728Val (c.2183A>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Glu728Val (c.2183A>T) in the general population?

AGRN p.Glu728Val (c.2183A>T) is low-frequency (popmax 4.27%, nfe) (gnomAD).

AGRN p.Glu728Val

c.2183A>T · rs113288277 · VCV128294

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.27%, nfe)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.233	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.27% European (non-Finnish) · 50,338/1,179,778 alleles

Filtering AF 4.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.22%

Overall 3.73% 60,098/1,612,466 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	7.36%	14
European (non-Finnish)grpmax	4.27%	23
Ashkenazi Jewishnot grpmax-eligible	4.26%	23
Remaining individualsnot grpmax-eligible	3.55%	28
Finnishnot grpmax-eligible	3.55%	28
Middle Eastern	3.02%	33
South Asian	2.38%	42
Admixed American	1.74%	58
African / African-American	0.6%	167
East Asian	0.317%	316

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu728Val
Coding: c.2183A>T
MANE Select: NM_198576
dbSNP: rs113288277
Type: single nucleotide variant
Location: chr1:1044368 (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 728: a UniProt-annotated variant site (in); the kazal-like 8 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.Glu728Lys 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-glu728val (accessed [today's date]).

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