Is AMN p.Gln236fs (c.683_705dup) pathogenic?

AMN p.Gln236fs (c.683705dup) is classified Pathogenic in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-27). Very rare (popmax 0.00716%, sas); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Gln236fs (c.683_705dup)?

AMN p.Gln236fs (c.683_705dup) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Gln236fs (c.683_705dup) in the general population?

AMN p.Gln236fs (c.683_705dup) is very rare (popmax 0.00716%, sas) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

AMN p.Gln236fs

c.683_705dup · rs1335752004 · VCV2738292

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00716%, sas)

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.5	GERP 0.93, phastCons 1
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00716% South Asian · 6/83,834 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00209%

Overall 0.000457% 7/1,531,216 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00716%	13,972
Remaining individualsnot grpmax-eligible	0.00168%	59,666

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.Gln236fs
Coding: c.683_705dup
MANE Select: NM_030943
dbSNP: rs1335752004
Type: Duplication
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 236: a disulfide bond; an α-helix; the vwfc domain

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

For Imerslund-Gräsbeck syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Finland)

Similar variants

AMN p.Ala372_Leu374dup Uncertain significance ★★ same condition
AMN p.Val442fs Uncertain significance ★★ same condition
AMN c.1257+20dup Benign/Likely benign ★★ same condition
AMN p.Gly448_Ala449dup Benign ★★ same condition
AMN p.Ala372fs Pathogenic ★ same condition
AMN p.Arg388fs Pathogenic ★ same condition
AMN p.Leu179fs Pathogenic ★ same condition
AMN p.Leu419fs 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-gln236fs (accessed [today's date]).

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