Is AMN p.Gly170fs (c.509del) pathogenic?

AMN p.Gly170fs (c.509del) is classified Likely pathogenic in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-23). Very rare (popmax 0.000933%, nfe); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Gly170fs (c.509del)?

AMN p.Gly170fs (c.509del) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Gly170fs (c.509del) in the general population?

AMN p.Gly170fs (c.509del) is very rare (popmax 0.000933%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

AMN p.Gly170fs

c.509del · VCV3576383

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 0.000933%, nfe)

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 5 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.6	GERP 1.1, phastCons 1
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,480 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000751% 12/1,598,596 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,328
European (non-Finnish)grpmax	0.000933%	107,225

Remaining individuals 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.Gly170fs
Coding: c.509del
MANE Select: NM_030943
Type: Deletion
Location: chr14:102928969 (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 170: 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 c.138_162+20del Likely pathogenic ★★ same condition
AMN c.208-13_211del Likely pathogenic ★★ same condition
AMN p.Gly5fs Pathogenic/Likely pathogenic ★★ same condition
AMN p.Gln12fs Pathogenic ★ same condition
AMN p.Phe104fs Likely pathogenic ★ same condition
AMN p.Pro381fs Likely pathogenic ★ same condition
AMN p.Pro42fs Likely pathogenic ★ same condition
AMN p.Gly170Asp Uncertain significance ★ ⚠ same residue

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-gly170fs (accessed [today's date]).

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