Is AGRN p.Arg1541Ter (c.4621C>T) pathogenic?

AGRN p.Arg1541Ter (c.4621C>T) is classified Likely pathogenic in AGRN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-05). Very rare (popmax 0.00135%, afr).

How common is AGRN p.Arg1541Ter (c.4621C>T) in the general population?

AGRN p.Arg1541Ter (c.4621C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

AGRN p.Arg1541Ter

c.4621C>T · rs750176911 · VCV489335

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 26 of 36
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP 0.24
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/74,282 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000254% 4/1,576,574 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,282
European (non-Finnish)	0.000258%	387,451

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.Arg1541Ter
Coding: c.4621C>T
MANE Select: NM_198576
dbSNP: rs750176911
Type: single nucleotide variant
Location: chr1:1049672 (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 1541: the laminin g-like 1 domain; a disulfide bond

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

Similar variants

AGRN p.Arg1541Gln Uncertain significance ★★ same residue
AGRN p.Arg1541Gly Uncertain significance ★ same residue
AGRN c.3632-1G>C Likely pathogenic ★★ same type
AGRN p.Arg1671Ter Pathogenic/Likely pathogenic ★★ same type
AGRN p.Arg834Ter Pathogenic/Likely pathogenic ★★ same type
AGRN p.Gly1582Arg Pathogenic ★★ same type
AGRN p.Gly1675Ser Pathogenic/Likely pathogenic ★★ same type
AGRN c.1177+4A>G Uncertain significance ★★ same type

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-arg1541ter (accessed [today's date]).

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