Is AGRN p.Cys1613= (c.4839C>T) pathogenic?

AGRN p.Cys1613= (c.4839C>T) is classified Benign/Likely benign in AGRN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). Rare (popmax 0.512%, nfe); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Cys1613= (c.4839C>T)?

AGRN p.Cys1613= (c.4839C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Cys1613= (c.4839C>T) in the general population?

AGRN p.Cys1613= (c.4839C>T) is rare (popmax 0.512%, nfe) (gnomAD).

AGRN p.Cys1613=

c.4839C>T · rs113020870 · VCV263189

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.512%, nfe)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.98	donor gain · deltas
Pangolin	Δ0.80	gain · loss 0.46 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.19	GERP -1.1, phastCons 0.97
Overall
CADD	19.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.512% European (non-Finnish) · 5,740/1,121,546 alleles

Filtering AF 0.501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.496%

Overall 0.422% 6,390/1,513,062 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.512%	195
Finnishnot grpmax-eligible	0.468%	214
Remaining individualsnot grpmax-eligible	0.288%	347
Admixed American	0.211%	474
African / African-American	0.0869%	1,150
South Asian	0.0536%	1,866
Ashkenazi Jewishnot grpmax-eligible	0.0461%	2,167
Middle Eastern	0.0181%	5,534

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.Cys1613=
Coding: c.4839C>T
MANE Select: NM_198576
dbSNP: rs113020870
Type: single nucleotide variant
Location: chr1:1049997 (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 1613: the egf-like 3 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.Cys1613Tyr 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-cys1613 (accessed [today's date]).

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