Is AMN p.Met69Lys (c.206T>A) pathogenic?

AMN p.Met69Lys (c.206T>A) is classified Pathogenic in AMN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-05-19). AlphaMissense: likely pathogenic (0.8281); Very rare (popmax 0.000508%, nfe); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Met69Lys (c.206T>A)?

AMN p.Met69Lys (c.206T>A) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Met69Lys (c.206T>A) in the general population?

AMN p.Met69Lys (c.206T>A) is very rare (popmax 0.000508%, 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.Met69Lys (c.206T>A)?

AlphaMissense predicts likely pathogenic (score 0.8281) — an in-silico prediction, not a clinical call.

AMN p.Met69Lys

c.206T>A · rs375774640 · VCV873126

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.8281	likely pathogenic ✓ concordant with ClinVar · top 8% in AMN
REVEL	0.616	indeterminate
SaProt	LLR -11.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	20.8	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 0.000508% European (non-Finnish) · 6/1,180,004 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,044 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.Met69Lys
Coding: c.206T>A
MANE Select: NM_030943
dbSNP: rs375774640
Type: single nucleotide variant
Location: chr14:102923978 (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 69: a UniProt-annotated variant site (in igs2; loss of interaction with cubn; strongly reduced cubn expression at the cell surface); a β-strand; the 'interaction with cubn' region; a disulfide bond

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.Met69Thr Uncertain significance ★★ ⚠ same residue
AMN p.Met69Ile 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
AMN c.844-1G>C Likely pathogenic ★★ same condition
AMN p.Thr41Ile 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-met69lys (accessed [today's date]).

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