Is AGRN p.Pro208= (c.624T>C) pathogenic?

AGRN p.Pro208= (c.624T>C) is classified Likely benign in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). Rare (popmax 0.218%, afr); Associated with congenital myasthenic syndrome 8.

What condition is associated with AGRN p.Pro208= (c.624T>C)?

AGRN p.Pro208= (c.624T>C) is associated with congenital myasthenic syndrome 8 (ClinVar).

How common is AGRN p.Pro208= (c.624T>C) in the general population?

AGRN p.Pro208= (c.624T>C) is rare (popmax 0.218%, afr) (gnomAD).

AGRN p.Pro208=

c.624T>C · rs371764695 · VCV706151

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.218%, 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 -16	GERP -2
Overall
CADD	0.462	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.218% African / African-American · 158/72,420 alleles

Filtering AF 0.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.18%

Overall 0.0133% 205/1,539,522 alleles · rare exomes 104/1,389,252 · genomes 101/150,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.218%	458
Remaining individualsnot grpmax-eligible	0.0267%	3,752
Admixed American	0.0157%	6,389
European (non-Finnish)	0.002%	49,881

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.Pro208=
Coding: c.624T>C
MANE Select: NM_198576
dbSNP: rs371764695
Type: single nucleotide variant
Location: chr1:1040777 (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 208: the kazal-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.Pro208Leu 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-pro208 (accessed [today's date]).

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