Is AMN p.Leu382Pro (c.1145T>C) pathogenic?

AMN p.Leu382Pro (c.1145T>C) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-06). AlphaMissense: likely benign (0.1331); Very rare (popmax 0.00356%, amr); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Leu382Pro (c.1145T>C)?

AMN p.Leu382Pro (c.1145T>C) is associated with Imerslund-Grasbeck syndrome type 2, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Leu382Pro (c.1145T>C) in the general population?

AMN p.Leu382Pro (c.1145T>C) is very rare (popmax 0.00356%, 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.Leu382Pro (c.1145T>C)?

AlphaMissense predicts likely benign (score 0.1331) — an in-silico prediction, not a clinical call.

AMN p.Leu382Pro

c.1145T>C · rs1232168405 · VCV2156563

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.1331	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.004	GERP 0.094, phastCons 0.012
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	20.4	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 0.00356% Admixed American · 1/28,120 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00196% 27/1,377,446 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00744%	13,432
Remaining individualsnot grpmax-eligible	0.0038%	26,296
Admixed Americangrpmax	0.00356%	28,120
European (non-Finnish)	0.00196%	51,146

Finnish 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.Leu382Pro
Coding: c.1145T>C
MANE Select: NM_030943
dbSNP: rs1232168405
Type: single nucleotide variant
Location: chr14:102930303 (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 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.Leu382= 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 p.Trp391Ter Pathogenic/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-leu382pro (accessed [today's date]).

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