Is AMN p.Arg323Trp (c.967C>T) pathogenic?

AMN p.Arg323Trp (c.967C>T) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely benign (0.1204); Very rare (popmax 0.00253%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Arg323Trp (c.967C>T)?

AMN p.Arg323Trp (c.967C>T) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Arg323Trp (c.967C>T) in the general population?

AMN p.Arg323Trp (c.967C>T) is very rare (popmax 0.00253%, nfe) (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.Arg323Trp (c.967C>T)?

AlphaMissense predicts likely benign (score 0.1204) — an in-silico prediction, not a clinical call.

AMN p.Arg323Trp

c.967C>T · rs759940999 · VCV2165197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00253%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.1204	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -12.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.96, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	24.1	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 0.00253% European (non-Finnish) · 29/1,146,814 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00153%

Overall 0.00187% 29/1,547,624 alleles · very rare

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.Arg323Trp
Coding: c.967C>T
MANE Select: NM_030943
dbSNP: rs759940999
Type: single nucleotide variant
Location: chr14:102930047 (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 — 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.Arg323= Likely benign ★★ 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-arg323trp (accessed [today's date]).

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