Is AMN p.Val152Leu (c.454G>C) pathogenic?

AMN p.Val152Leu (c.454G>C) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: ambiguous (0.5543); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Val152Leu (c.454G>C)?

AMN p.Val152Leu (c.454G>C) is associated with Inborn genetic diseases (ClinVar).

How common is AMN p.Val152Leu (c.454G>C) in the general population?

AMN p.Val152Leu (c.454G>C) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about AMN p.Val152Leu (c.454G>C)?

AlphaMissense predicts ambiguous (score 0.5543) — an in-silico prediction, not a clinical call.

AMN p.Val152Leu

c.454G>C · rs201055900 · VCV3116055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5543	ambiguous
REVEL	0.601	indeterminate
SaProt	LLR -11.48	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	25.9	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 0.00271% European (non-Finnish) · 32/1,179,794 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00218% 35/1,602,016 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,198
European (non-Finnish)grpmax	0.00271%	36,869
African / African-American	0.00133%	74,924

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val152Leu
Coding: c.454G>C
MANE Select: NM_030943
dbSNP: rs201055900
Type: single nucleotide variant
Location: chr14:102928916 (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 152: a disulfide bond

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

Similar variants

AMN p.Val152Met Uncertain significance ★ ⚠ same residue
AMN p.Val152= Likely benign ★ same residue
AMN p.Ala238Thr Uncertain significance ★★ ⚠ same condition
AMN p.Ala44Thr Uncertain significance ★★ ⚠ same condition
AMN p.Arg271Trp Uncertain significance ★★ ⚠ same condition
AMN p.Arg424Gly Uncertain significance ★★ ⚠ same condition
AMN p.Cys250Trp Uncertain significance ★★ ⚠ same condition
AMN p.Gln288His 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-val152leu (accessed [today's date]).

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