Is AMN p.Leu227His (c.680T>A) pathogenic?

AMN p.Leu227His (c.680T>A) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: ambiguous (0.3676); Absent from gnomAD v4.1; Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Leu227His (c.680T>A)?

AMN p.Leu227His (c.680T>A) is associated with Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Leu227His (c.680T>A) in the general population?

AMN p.Leu227His (c.680T>A) is absent from gnomAD v4.1 (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.Leu227His (c.680T>A)?

AlphaMissense predicts ambiguous (score 0.3676) — an in-silico prediction, not a clinical call.

AMN p.Leu227His

c.680T>A · VCV3576391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3676 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.3676	ambiguous
REVEL	0.611	indeterminate
SaProt	LLR -10.84	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.93, 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AMN
Protein: p.Leu227His
Coding: c.680T>A
MANE Select: NM_030943
Type: single nucleotide variant
Location: chr14:102929456 (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 227: a disulfide bond; the vwfc domain

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-leu227his (accessed [today's date]).

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