Is AMN p.Arg424Gly (c.1270C>G) pathogenic?

AMN p.Arg424Gly (c.1270C>G) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0714); Ultra-rare (popmax 0.059%, amr); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Arg424Gly (c.1270C>G)?

AMN p.Arg424Gly (c.1270C>G) is associated with Inborn genetic diseases, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Arg424Gly (c.1270C>G) in the general population?

AMN p.Arg424Gly (c.1270C>G) is ultra-rare (popmax 0.059%, amr) (gnomAD).

What do computational predictors say about AMN p.Arg424Gly (c.1270C>G)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

AMN p.Arg424Gly

c.1270C>G · rs778728963 · VCV2147522

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.059%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -1.1, phastCons 0.001
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	19.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.059% Admixed American · 33/55,890 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0377%

Overall 0.00834% 132/1,582,322 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.059%	1,694
African / African-American	0.0175%	5,698
Remaining individualsnot grpmax-eligible	0.0147%	6,799
European (non-Finnish)	0.00643%	15,551
South Asian	0.0023%	43,446

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.Arg424Gly
Coding: c.1270C>G
MANE Select: NM_030943
dbSNP: rs778728963
Type: single nucleotide variant
Location: chr14:102930588 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome

Similar variants

AMN p.Arg424= Likely benign ★ 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
AMN p.Trp391Ter Pathogenic/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-arg424gly (accessed [today's date]).

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