Is AMN p.Gly448Glu (c.1343G>A) pathogenic?

AMN p.Gly448Glu (c.1343G>A) is classified Conflicting classifications of pathogenicity in AMN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.0762); Rare (popmax 0.14%, mid); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Gly448Glu (c.1343G>A)?

AMN p.Gly448Glu (c.1343G>A) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Gly448Glu (c.1343G>A) in the general population?

AMN p.Gly448Glu (c.1343G>A) is rare (popmax 0.14%, mid) (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.Gly448Glu (c.1343G>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

AMN p.Gly448Glu

c.1343G>A · rs777560818 · VCV1022286

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.14%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -5.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.043	GERP -1.5, phastCons 0.18
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	1.332	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.14% Middle Eastern · 8/5,722 alleles

Filtering AF 0.0695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0507%

Overall 0.0194% 310/1,595,034 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.185%	541
Middle Easterngrpmax	0.14%	715
Remaining individualsnot grpmax-eligible	0.0633%	1,581
Admixed American	0.038%	2,632
European (non-Finnish)	0.015%	6,660
South Asian	0.0102%	9,801
East Asian	0.00228%	43,824
African / African-American	0.00134%	74,658

Ashkenazi Jewish 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.Gly448Glu
Coding: c.1343G>A
MANE Select: NM_030943
dbSNP: rs777560818
Type: single nucleotide variant
Location: chr14:102930661 (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.Gly448= Likely benign ★ same residue
AMN p.Gly448_Ala449dup Benign ★★ same residue
AMN p.Gly448Arg Likely benign ★ 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

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-gly448glu (accessed [today's date]).

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