Is AGRN p.Pro500= (c.1500T>C) pathogenic?

AGRN p.Pro500= (c.1500T>C) is classified Benign in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Rare (popmax 0.417%, sas); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Pro500= (c.1500T>C)?

AGRN p.Pro500= (c.1500T>C) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Pro500= (c.1500T>C) in the general population?

AGRN p.Pro500= (c.1500T>C) is rare (popmax 0.417%, sas) (gnomAD).

AGRN p.Pro500=

c.1500T>C · rs373770321 · VCV704483

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.417%, sas)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.6
Overall
CADD	0.166	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.417% South Asian · 378/90,602 alleles

Filtering AF 0.382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.369%

Overall 0.0256% 413/1,610,690 alleles · rare exomes 392/1,458,430 · genomes 21/152,260 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.417%	240
Remaining individualsnot grpmax-eligible	0.0497%	2,013
African / African-American	0.00133%	75,014
European (non-Finnish)	0.000254%	393,031

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.Pro500=
Coding: c.1500T>C
MANE Select: NM_198576
dbSNP: rs373770321
Type: single nucleotide variant
Location: chr1:1043354 (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 500: 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 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
AGRN c.4879+4G>A 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-pro500 (accessed [today's date]).

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