Is AMN p.Glu450Gly (c.1349A>G) pathogenic?

AMN p.Glu450Gly (c.1349A>G) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-13). AlphaMissense: likely benign (0.1555); Rare (popmax 0.197%, afr); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Glu450Gly (c.1349A>G)?

AMN p.Glu450Gly (c.1349A>G) is associated with Imerslund-Grasbeck syndrome type 2, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Glu450Gly (c.1349A>G) in the general population?

AMN p.Glu450Gly (c.1349A>G) is rare (popmax 0.197%, afr) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

What do computational predictors say about AMN p.Glu450Gly (c.1349A>G)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

AMN p.Glu450Gly

c.1349A>G · rs370794142 · VCV940760

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.197% African / African-American · 143/72,714 alleles

Filtering AF 0.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.16%

Overall 0.0131% 206/1,575,246 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.197%	508
Middle Eastern	0.036%	2,778
South Asian	0.0206%	4,863
Admixed American	0.014%	7,141
Remaining individualsnot grpmax-eligible	0.0132%	7,598
European (non-Finnish)	0.00233%	42,935

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.Glu450Gly
Coding: c.1349A>G
MANE Select: NM_030943
dbSNP: rs370794142
Type: single nucleotide variant
Location: chr14:102930667 (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.Glu450= Likely benign ★ same residue
AMN p.Glu450fs Uncertain significance ★ same residue
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
AMN c.844-1G>C Likely pathogenic ★★ same condition
AMN p.Thr41Ile 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-glu450gly (accessed [today's date]).

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