Is AMN p.Arg323= (c.969G>A) pathogenic?

AMN p.Arg323= (c.969G>A) is classified Likely benign in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-18). Very rare (popmax 0.00785%, amr); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Arg323= (c.969G>A)?

AMN p.Arg323= (c.969G>A) is associated with Imerslund-Grasbeck syndrome type 2, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Arg323= (c.969G>A) in the general population?

AMN p.Arg323= (c.969G>A) is very rare (popmax 0.00785%, amr) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

AMN p.Arg323=

c.969G>A · rs899760936 · VCV1152542

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00785%, amr)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.83	GERP 0.96, phastCons 1
Overall
CADD	8.916	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00785% Admixed American · 4/50,958 alleles

Filtering AF 0.00263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00153%

Overall 0.000582% 9/1,546,832 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00785%	12,740
Remaining individualsnot grpmax-eligible	0.00668%	14,960
European (non-Finnish)	8.72e-05%	1,146,526

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.Arg323=
Coding: c.969G>A
MANE Select: NM_030943
dbSNP: rs899760936
Type: single nucleotide variant
Location: chr14:102930049 (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 323: an α-helix

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.Arg323Trp Uncertain significance ★ ⚠ same residue
AMN p.Arg323fs Pathogenic ★ same residue
AMN p.Arg323Leu Uncertain significance ★ ⚠ same residue
AMN p.Arg323Pro 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

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-arg323 (accessed [today's date]).

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