Is AMN p.Ala303= (c.909C>T) pathogenic?

AMN p.Ala303= (c.909C>T) is classified Benign/Likely benign in AMN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-22). Ultra-rare (popmax 0.0542%, sas); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Ala303= (c.909C>T)?

AMN p.Ala303= (c.909C>T) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Ala303= (c.909C>T) in the general population?

AMN p.Ala303= (c.909C>T) is ultra-rare (popmax 0.0542%, sas) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AMN p.Ala303=

c.909C>T · rs373382273 · VCV695844

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0542%, sas)

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -1.9
Overall
CADD	1.686	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0542% South Asian · 46/84,832 alleles

Filtering AF 0.0417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0373%

Overall 0.0346% 541/1,563,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0542%	1,844
European (non-Finnish)	0.0394%	2,538
African / African-American	0.0271%	3,684
Remaining individualsnot grpmax-eligible	0.0215%	4,660
Finnishnot grpmax-eligible	0.00506%	19,763
East Asian	0.0048%	20,815
Admixed American	0.00377%	26,533

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.Ala303=
Coding: c.909C>T
MANE Select: NM_030943
dbSNP: rs373382273
Type: single nucleotide variant
Location: chr14:102929989 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome type 2

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 p.Trp391Ter Pathogenic/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-ala303 (accessed [today's date]).

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