Is AP4M1 p.Phe409Leu (c.1225T>C) pathogenic?

AP4M1 p.Phe409Leu (c.1225T>C) is classified Conflicting classifications of pathogenicity in AP4M1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-08-09). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 0.00333%, amr); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Phe409Leu (c.1225T>C)?

AP4M1 p.Phe409Leu (c.1225T>C) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Phe409Leu (c.1225T>C) in the general population?

AP4M1 p.Phe409Leu (c.1225T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about AP4M1 p.Phe409Leu (c.1225T>C)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

AP4M1 p.Phe409Leu

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.1225T>C · rs760907496 · VCV522649

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic · top 1% in AP4M1
REVEL	0.742	pathogenic-leaning
SaProt	LLR -12.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	25.7	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 0.00333% Admixed American · 2/60,026 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000479% 7/1,461,696 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,013
European (non-Finnish)	0.000424%	236,008

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: AP4M1
Protein: p.Phe409Leu
Coding: c.1225T>C
MANE Select: NM_004722
dbSNP: rs760907496
Type: single nucleotide variant
Location: chr7:100106745 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 409: 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 p.Phe409Ser Uncertain significance ★ ⚠ same residue
AP4M1 p.Phe409= Likely benign ★ same residue
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

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-phe409leu (accessed [today's date]).

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