Is AGRN p.Ser595Pro (c.1783T>C) pathogenic?

AGRN p.Ser595Pro (c.1783T>C) is classified Uncertain significance in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). Ultra-rare (popmax 0.0523%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AGRN p.Ser595Pro (c.1783T>C)?

AGRN p.Ser595Pro (c.1783T>C) is associated with Inborn genetic diseases (ClinVar).

How common is AGRN p.Ser595Pro (c.1783T>C) in the general population?

AGRN p.Ser595Pro (c.1783T>C) is ultra-rare (popmax 0.0523%, nfe) (gnomAD).

AGRN p.Ser595Pro

c.1783T>C · rs767861466 · VCV2397897

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0523%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.462	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 0.84
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	17.77	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0523% European (non-Finnish) · 617/1,179,704 alleles

Filtering AF 0.0488% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0475%

Overall 0.0391% 626/1,600,530 alleles · ultra-rare exomes 606/1,448,684 · genomes 20/151,846 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0523%	1,912
Remaining individualsnot grpmax-eligible	0.0112%	8,911
Admixed American	0.00167%	59,964
African / African-American	0.00134%	74,736

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.Ser595Pro
Coding: c.1783T>C
MANE Select: NM_198576
dbSNP: rs767861466
Type: single nucleotide variant
Location: chr1:1043717 (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 595: the kazal-like 6 domain

Full AGRN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGRN p.Ser595Leu Uncertain significance ★ same residue
AGRN p.Ala1012Thr Uncertain significance ★★ same condition
AGRN p.Ala1056Thr Uncertain significance ★★ same condition
AGRN p.Ala1304Thr Uncertain significance ★★ same condition
AGRN p.Ala1325Gly Uncertain significance ★★ same condition
AGRN p.Ala1372Thr Uncertain significance ★★ same condition
AGRN p.Ala1737Val Uncertain significance ★★ same condition
AGRN p.Ala302Gly 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-ser595pro (accessed [today's date]).

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