Is AMN p.Asp331Glu (c.993C>A) pathogenic?

AMN p.Asp331Glu (c.993C>A) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: ambiguous (0.4335); Very rare (popmax 0.00197%, amr); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Asp331Glu (c.993C>A)?

AMN p.Asp331Glu (c.993C>A) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Asp331Glu (c.993C>A) in the general population?

AMN p.Asp331Glu (c.993C>A) is very rare (popmax 0.00197%, 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.Asp331Glu (c.993C>A)?

AlphaMissense predicts ambiguous (score 0.4335) — an in-silico prediction, not a clinical call.

AMN p.Asp331Glu

c.993C>A · VCV3576406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00197%, amr)

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.4335	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -7.23	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.54	GERP 0.96
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	19.89	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 0.00197% Admixed American · 1/50,800 alleles

Overall 0.000144% 2/1,389,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00197%	50,800
South Asian	0.0012%	83,466

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.Asp331Glu
Coding: c.993C>A
MANE Select: NM_030943
Type: single nucleotide variant
Location: chr14:102930073 (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 331: 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 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
AMN c.651+3G>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-asp331glu (accessed [today's date]).

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