Is AMN p.Glu76fs (c.223_226dup) pathogenic?

AMN p.Glu76fs (c.223226dup) is classified Likely pathogenic in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). Very rare (popmax 6.22e-05%); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Glu76fs (c.223_226dup)?

AMN p.Glu76fs (c.223_226dup) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Glu76fs (c.223_226dup) in the general population?

AMN p.Glu76fs (c.223_226dup) is very rare (popmax 6.22e-05%) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

AMN p.Glu76fs

c.223_226dup · VCV3576376

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.22e-05%)

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.95	GERP -2.4, phastCons 0.008

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.22e-05%

Overall 6.22e-05% 1/1,606,474 alleles · very rare exomes 1/1,454,322 · genomes 0/152,152 · joint denominator

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.Glu76fs
Coding: c.223_226dup
MANE Select: NM_030943
Type: Duplication
Location: chr14:102928440 (GRCh38)
Gene constraint: LOEUF 1.446 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.78 · 1 PDB
Residue 76: a β-strand; the 'interaction with cubn' region

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

Disease context

Imerslund-Grasbeck syndrome type 2 — 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.Ser349fs Likely pathogenic ★★ same condition
AMN p.Ala372_Leu374dup Uncertain significance ★★ same condition
AMN p.Val378_Ala379insLeuLeuVal 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.Ser165fs Pathogenic ★ same condition
AMN c.761-15dup 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/amn-p-glu76fs (accessed [today's date]).

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