Is AGRN p.Pro565= (c.1695C>T) pathogenic?

AGRN p.Pro565= (c.1695C>T) is classified Likely benign in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). Ultra-rare (popmax 0.02%, amr); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Pro565= (c.1695C>T)?

AGRN p.Pro565= (c.1695C>T) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Pro565= (c.1695C>T) in the general population?

AGRN p.Pro565= (c.1695C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

AGRN p.Pro565=

c.1695C>T · rs778573221 · VCV1129786

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, 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 Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9.1	GERP -2.3
Overall
CADD	0.664	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/59,990 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00655% 105/1,603,546 alleles · ultra-rare exomes 97/1,451,348 · genomes 8/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,999
European (non-Finnish)	0.00754%	13,256
Remaining individualsnot grpmax-eligible	0.00481%	20,802
African / African-American	0.00134%	74,900

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.Pro565=
Coding: c.1695C>T
MANE Select: NM_198576
dbSNP: rs778573221
Type: single nucleotide variant
Location: chr1:1043629 (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 565: the kazal-like 6 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.Pro565Ser 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-pro565 (accessed [today's date]).

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