Is AMN p.Trp391Ter (c.1173G>A) pathogenic?

AMN p.Trp391Ter (c.1173G>A) is classified Pathogenic/Likely pathogenic in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-25). Very rare (popmax 0.00201%, amr); Associated with AMN-related disorder.

What condition is associated with AMN p.Trp391Ter (c.1173G>A)?

AMN p.Trp391Ter (c.1173G>A) is associated with AMN-related disorder, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Trp391Ter (c.1173G>A) in the general population?

AMN p.Trp391Ter (c.1173G>A) is very rare (popmax 0.00201%, amr) (gnomAD).

AMN p.Trp391Ter

c.1173G>A · rs1401073549 · VCV2628532

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00201%, amr)

Conditions

AMN-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 12
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Overall
CADD	37.0	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 0.00201% Admixed American · 1/49,692 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000324%

Overall 0.00079% 12/1,519,068 alleles · very rare exomes 9/1,366,940 · genomes 3/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00201%	49,692
African / African-American	0.00141%	71,002
European (non-Finnish)	0.000877%	113,970

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.Trp391Ter
Coding: c.1173G>A
MANE Select: NM_030943
dbSNP: rs1401073549
Type: single nucleotide variant
Location: chr14:102930409 (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

AMN-related disorder

Also linked: Imerslund-Grasbeck syndrome

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-trp391ter (accessed [today's date]).

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