Is AGRN p.Thr1684Pro (c.5050A>C) pathogenic?

AGRN p.Thr1684Pro (c.5050A>C) is classified Uncertain significance in AGRN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-11). Absent from gnomAD v4.1; Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Thr1684Pro (c.5050A>C)?

AGRN p.Thr1684Pro (c.5050A>C) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Thr1684Pro (c.5050A>C) in the general population?

AGRN p.Thr1684Pro (c.5050A>C) is absent from gnomAD v4.1 (gnomAD).

AGRN p.Thr1684Pro

c.5050A>C · rs2522787955 · VCV2004776

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.592	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.68, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 8,500 bp · p 0.41 · regional, not allelic
Overall
CADD	19.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AGRN
Protein: p.Thr1684Pro
Coding: c.5050A>C
MANE Select: NM_198576
dbSNP: rs2522787955
Type: single nucleotide variant
Location: chr1:1050500 (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 1684: the laminin g-like 2 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.Thr1684Met Uncertain significance ★★ same residue
AGRN p.Thr1684= Likely benign ★ same residue
AGRN p.Thr1684del 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

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-thr1684pro (accessed [today's date]).

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