Is AGRN p.Asp246= (c.738C>T) pathogenic?

AGRN p.Asp246= (c.738C>T) is classified Benign/Likely benign in AGRN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). Low-frequency (popmax 2.02%, afr); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Asp246= (c.738C>T)?

AGRN p.Asp246= (c.738C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Asp246= (c.738C>T) in the general population?

AGRN p.Asp246= (c.738C>T) is low-frequency (popmax 2.02%, afr) (gnomAD).

AGRN p.Asp246=

c.738C>T · rs536085218 · VCV263203

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.02%, afr)

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 0.52	GERP -2.3, phastCons 1
Overall
CADD	6.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.02% African / African-American · 1,319/65,168 alleles

Filtering AF 1.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9%

Overall 0.105% 1,509/1,438,034 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.02%	49
Admixed American	0.21%	476
Middle Eastern	0.198%	504
Remaining individualsnot grpmax-eligible	0.146%	683
South Asian	0.00671%	14,910
European (non-Finnish)	0.00154%	64,758

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.Asp246=
Coding: c.738C>T
MANE Select: NM_198576
dbSNP: rs536085218
Type: single nucleotide variant
Location: chr1:1041183 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.79 · 1 PDB

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-asp246 (accessed [today's date]).

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