Is AMN p.Leu419fs (c.1255dup) pathogenic?

AMN p.Leu419fs (c.1255dup) is classified Pathogenic in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-31). Very rare (popmax 0.000525%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Leu419fs (c.1255dup)?

AMN p.Leu419fs (c.1255dup) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Leu419fs (c.1255dup) in the general population?

AMN p.Leu419fs (c.1255dup) is very rare (popmax 0.000525%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AMN p.Leu419fs

c.1255dup · rs1303690601 · VCV2902916

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000525%, nfe)

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (11 of 12, 3 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP -1.2, phastCons 0.92

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000525% European (non-Finnish) · 6/1,142,986 alleles

Filtering AF 0.000189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000456% 7/1,536,070 alleles · very rare exomes 7/1,383,778 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00168%	59,570
European (non-Finnish)grpmax	0.000525%	190,498

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AMN
Protein: p.Leu419fs
Coding: c.1255dup
MANE Select: NM_030943
dbSNP: rs1303690601
Type: Duplication
Location: chr14:102930490 (GRCh38)
Gene constraint: LOEUF 1.446 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.78 · 1 PDB

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

Disease context

Imerslund-Grasbeck syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Imerslund-Gräsbeck syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Finland)

Similar variants

AMN p.Leu419= Uncertain significance ★ same residue
AMN p.Ala372_Leu374dup Uncertain significance ★★ same condition
AMN p.Val442fs Uncertain significance ★★ same condition
AMN c.1257+20dup Benign/Likely benign ★★ same condition
AMN p.Gly448_Ala449dup Benign ★★ same condition
AMN p.Ala372fs Pathogenic ★ same condition
AMN p.Arg388fs Pathogenic ★ same condition
AMN p.Gln236fs Pathogenic ★ 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/amn-p-leu419fs (accessed [today's date]).

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