Is AGRN p.Ser614= (c.1842C>T) pathogenic?

AGRN p.Ser614= (c.1842C>T) is classified Likely benign in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). Ultra-rare (popmax 0.0117%, amr); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Ser614= (c.1842C>T)?

AGRN p.Ser614= (c.1842C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Ser614= (c.1842C>T) in the general population?

AGRN p.Ser614= (c.1842C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

AGRN p.Ser614=

c.1842C>T · rs774748438 · VCV702574

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

congenital myasthenic syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.3	GERP -2
Overall
CADD	0.955	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,948 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00161% 26/1,611,210 alleles · ultra-rare exomes 23/1,459,492 · genomes 3/151,718 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,564
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,860
South Asian	0.00329%	30,356
Remaining individualsnot grpmax-eligible	0.0016%	62,442
African / African-American	0.00134%	74,722
European (non-Finnish)	0.000932%	107,252

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.Ser614=
Coding: c.1842C>T
MANE Select: NM_198576
dbSNP: rs774748438
Type: single nucleotide variant
Location: chr1:1043866 (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 614: 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 p.Ser614Phe 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-ser614 (accessed [today's date]).

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