Is AMN p.Leu324Pro (c.971T>C) pathogenic?

AMN p.Leu324Pro (c.971T>C) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). AlphaMissense: likely pathogenic (0.782); Very rare (popmax 0.00393%, amr); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Leu324Pro (c.971T>C)?

AMN p.Leu324Pro (c.971T>C) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Leu324Pro (c.971T>C) in the general population?

AMN p.Leu324Pro (c.971T>C) is very rare (popmax 0.00393%, amr) (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.Leu324Pro (c.971T>C)?

AlphaMissense predicts likely pathogenic (score 0.782) — an in-silico prediction, not a clinical call.

AMN p.Leu324Pro

c.971T>C · VCV3576404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00393%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.782	likely pathogenic · top 10% in AMN
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 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	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00393% Admixed American · 2/50,938 alleles

Filtering AF 0.000651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000244%

Overall 0.000129% 2/1,546,676 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.Leu324Pro
Coding: c.971T>C
MANE Select: NM_030943
Type: single nucleotide variant
Location: chr14:102930051 (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 324: 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

For Imerslund-Gräsbeck syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Finland)

Similar variants

AMN p.Leu324= 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
AMN p.Thr41Ile Likely pathogenic ★★ ⚠ same condition
AMN c.296-3C>T Uncertain significance ★★ 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-leu324pro (accessed [today's date]).

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