Is AP4M1 p.Leu189Trp (c.566T>G) pathogenic?

AP4M1 p.Leu189Trp (c.566T>G) is classified Uncertain significance in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely pathogenic (0.9657); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Leu189Trp (c.566T>G)?

AP4M1 p.Leu189Trp (c.566T>G) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Leu189Trp (c.566T>G) in the general population?

AP4M1 p.Leu189Trp (c.566T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP4M1 p.Leu189Trp (c.566T>G)?

AlphaMissense predicts likely pathogenic (score 0.9657) — an in-silico prediction, not a clinical call.

AP4M1 p.Leu189Trp

Q: How is Severe intellectual disability and progressive spastic paraplegia inherited?

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

c.566T>G · rs2116643609 · VCV1333549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9657 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
AlphaMissense	0.9657	likely pathogenic · top 10% in AP4M1
REVEL	0.391	indeterminate
SaProt	LLR -15.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP4M1
Protein: p.Leu189Trp
Coding: c.566T>G
MANE Select: NM_004722
dbSNP: rs2116643609
Type: single nucleotide variant
Location: chr7:100104114 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 189: the mhd domain; a β-strand

Full AP4M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 50 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability and progressive spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AP4M1 c.1137+1G>T Pathogenic/Likely pathogenic ★★ same condition
AP4M1 c.930-1G>C Likely pathogenic ★★ same condition
AP4M1 p.Arg268Ter Pathogenic ★★ same condition
AP4M1 p.Arg306Ter Pathogenic ★★ same condition
AP4M1 p.Arg318Ter Pathogenic ★★ same condition
AP4M1 p.Arg338Ter Pathogenic/Likely pathogenic ★★ same condition
AP4M1 p.Cys319Arg Pathogenic/Likely pathogenic ★★ same condition
AP4M1 p.Gln183Ter 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/ap4m1-p-leu189trp (accessed [today's date]).

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