Is AMN p.Gly46del (c.134GCG[1]) pathogenic?

AMN p.Gly46del (c.134GCG[1]) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). Very rare (popmax 0.00267%, afr); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Gly46del (c.134GCG[1])?

AMN p.Gly46del (c.134GCG[1]) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Gly46del (c.134GCG[1]) in the general population?

AMN p.Gly46del (c.134GCG[1]) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

AMN p.Gly46del

c.134GCG[1] · VCV3576370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.45	GERP 0.21
Overall
CADD	15.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,930 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,612,568 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,465
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	0.000763%	131,094

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.Gly46del
Coding: c.134GCG[1]
MANE Select: NM_030943
Type: Microsatellite
Location: chr14:102923799 (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 46: a β-strand; a disulfide bond

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.Gly46Ser Uncertain significance ★ ⚠ same residue
AMN c.44-7_44-5del Uncertain significance ★★ same condition
AMN c.138_162+20del Likely pathogenic ★★ same condition
AMN c.208-13_211del Likely pathogenic ★★ same condition
AMN c.208-1G>C Pathogenic/Likely pathogenic ★★ same condition
AMN c.296-1G>A Likely pathogenic ★★ same condition
AMN c.44-1G>A Likely pathogenic ★★ same condition
AMN c.760+1G>A Likely 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-gly46del (accessed [today's date]).

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