Is AGRN p.Phe1377= (c.4131C>T) pathogenic?

AGRN p.Phe1377= (c.4131C>T) is classified Benign/Likely benign in AGRN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-18). Rare (popmax 0.859%, afr); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Phe1377= (c.4131C>T)?

AGRN p.Phe1377= (c.4131C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Phe1377= (c.4131C>T) in the general population?

AGRN p.Phe1377= (c.4131C>T) is rare (popmax 0.859%, afr) (gnomAD).

AGRN p.Phe1377=

c.4131C>T · rs368555478 · VCV392687

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.859%, 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 -9.3	GERP -2.5
Overall
CADD	0.246	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.859% African / African-American · 627/73,034 alleles

Filtering AF 0.803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.781%

Overall 0.051% 788/1,545,438 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.859%	116
Remaining individualsnot grpmax-eligible	0.0804%	1,243
Admixed American	0.0708%	1,413
Middle Eastern	0.0647%	1,545
European (non-Finnish)	0.00603%	16,594
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,604
East Asian	0.00242%	41,354
South Asian	0.00237%	42,126

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.Phe1377=
Coding: c.4131C>T
MANE Select: NM_198576
dbSNP: rs368555478
Type: single nucleotide variant
Location: chr1:1048892 (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 1377: the laminin g-like 1 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.Phe1377Leu 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-phe1377 (accessed [today's date]).

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