Is AMN1 p.Ile224Leu (c.670A>T) pathogenic?

AMN1 p.Ile224Leu (c.670A>T) is classified Uncertain significance in AMN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.3509); Very rare (popmax 0.00167%, amr).

How common is AMN1 p.Ile224Leu (c.670A>T) in the general population?

AMN1 p.Ile224Leu (c.670A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about AMN1 p.Ile224Leu (c.670A>T)?

AlphaMissense predicts ambiguous (score 0.3509) — an in-silico prediction, not a clinical call.

AMN1 p.Ile224Leu

c.670A>T · VCV4092305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3509	ambiguous
REVEL	0.181	moderately benign-leaning
SaProt	LLR -6.35	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 57 kb · p 0.00046 · regional, not allelic
Overall
CADD	24.8	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

Grpmax group 0.00167% Admixed American · 1/59,980 alleles

Overall 6.84e-05% 1/1,461,146 alleles · very rare

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: AMN1
Protein: p.Ile224Leu
Coding: c.670A>T
MANE Select: NM_001113402
Type: single nucleotide variant
Location: chr12:31689040 (GRCh38)
Gene constraint: LOEUF 0.838 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.56

Full AMN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMN1 p.Ala109Ser Uncertain significance ★ ⚠ same type
AMN1 p.Arg223Pro Uncertain significance ★ ⚠ same type
AMN1 p.Arg3Cys Uncertain significance ★ ⚠ same type
AMN1 p.Arg5Gln Uncertain significance ★ ⚠ same type
AMN1 p.Arg69Leu Uncertain significance ★ ⚠ same type
AMN1 p.Arg6Pro Uncertain significance ★ ⚠ same type
AMN1 p.Arg85Gly Uncertain significance ★ ⚠ same type
AMN1 p.Asn206Ser Uncertain significance ★ ⚠ same type

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/amn1-p-ile224leu (accessed [today's date]).

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