Is AGRN p.Ala648= (c.1944C>T) pathogenic?

AGRN p.Ala648= (c.1944C>T) is classified Likely benign in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-20). Very rare (popmax 0.00447%, eas); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Ala648= (c.1944C>T)?

AGRN p.Ala648= (c.1944C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Ala648= (c.1944C>T) in the general population?

AGRN p.Ala648= (c.1944C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

AGRN p.Ala648=

c.1944C>T · rs535437903 · VCV2722462

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

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 -9.8	GERP -2
Overall
CADD	0.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% East Asian · 2/44,760 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000685% 11/1,605,798 alleles · very rare exomes 9/1,453,478 · genomes 2/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,380
African / African-American	0.004%	24,991
European (non-Finnish)	0.000509%	196,461

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.Ala648=
Coding: c.1944C>T
MANE Select: NM_198576
dbSNP: rs535437903
Type: single nucleotide variant
Location: chr1:1043968 (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 648: the kazal-like 7 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-ala648 (accessed [today's date]).

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