Is AGRN p.Ser981Phe (c.2942C>T) pathogenic?

AGRN p.Ser981Phe (c.2942C>T) is classified Uncertain significance in AGRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-01). Very rare (popmax 0.00517%, nfe); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Ser981Phe (c.2942C>T)?

AGRN p.Ser981Phe (c.2942C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Ser981Phe (c.2942C>T) in the general population?

AGRN p.Ser981Phe (c.2942C>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

AGRN p.Ser981Phe

c.2942C>T · rs368058639 · VCV1491603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.198	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.049	GERP 0.02
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	14.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00517% European (non-Finnish) · 61/1,179,880 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00403% 65/1,612,438 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,342
Remaining individualsnot grpmax-eligible	0.0032%	31,223
Admixed American	0.00167%	59,978
African / African-American	0.00133%	74,914

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.Ser981Phe
Coding: c.2942C>T
MANE Select: NM_198576
dbSNP: rs368058639
Type: single nucleotide variant
Location: chr1:1046427 (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 p.Ser981Pro Uncertain significance ★ same residue
AGRN p.Ser981= Likely benign ★ 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

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-ser981phe (accessed [today's date]).

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