Is AMN p.Val442fs (c.1308_1323dup) pathogenic?

AMN p.Val442fs (c.13081323dup) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-22). Very rare (popmax 6.96e-05%); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Val442fs (c.1308_1323dup)?

AMN p.Val442fs (c.1308_1323dup) is associated with Imerslund-Grasbeck syndrome type 2, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Val442fs (c.1308_1323dup) in the general population?

AMN p.Val442fs (c.1308_1323dup) is very rare (popmax 6.96e-05%) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

AMN p.Val442fs

c.1308_1323dup · rs2139314176 · VCV1510483

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.96e-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	escapes	premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.069	GERP -2.2

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.96e-05%

Overall 6.96e-05% 1/1,436,430 alleles · very rare

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.Val442fs
Coding: c.1308_1323dup
MANE Select: NM_030943
dbSNP: rs2139314176
Type: Duplication
Location: chr14:102930624 (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 type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

AMN p.Val442Ile Uncertain significance ★★ ⚠ same residue
AMN p.Ser349fs Likely pathogenic ★★ same condition
AMN p.Ala372_Leu374dup Uncertain significance ★★ same condition
AMN p.Val378_Ala379insLeuLeuVal 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

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-val442fs (accessed [today's date]).

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