Is AP4M1 p.Ser9Phe (c.26C>T) pathogenic?

AP4M1 p.Ser9Phe (c.26C>T) is classified Uncertain significance in AP4M1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-24). AlphaMissense: likely pathogenic (0.9787); Very rare (popmax 0.00446%, eas); Associated with hereditary spastic paraplegia 50.

What condition is associated with AP4M1 p.Ser9Phe (c.26C>T)?

AP4M1 p.Ser9Phe (c.26C>T) is associated with hereditary spastic paraplegia 50 (ClinVar).

How common is AP4M1 p.Ser9Phe (c.26C>T) in the general population?

AP4M1 p.Ser9Phe (c.26C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about AP4M1 p.Ser9Phe (c.26C>T)?

AlphaMissense predicts likely pathogenic (score 0.9787) — an in-silico prediction, not a clinical call.

AP4M1 p.Ser9Phe

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.26C>T · rs751068724 · VCV560945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 50

Computational evidence

Protein change
AlphaMissense	0.9787	likely pathogenic · top 7% in AP4M1
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -14.83	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00446% East Asian · 2/44,892 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00204% 33/1,613,778 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,002
East Asiangrpmax	0.00446%	22,446
Remaining individualsnot grpmax-eligible	0.0032%	31,234
European (non-Finnish)	0.00212%	47,196

Finnish 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: AP4M1
Protein: p.Ser9Phe
Coding: c.26C>T
MANE Select: NM_004722
dbSNP: rs751068724
Type: single nucleotide variant
Location: chr7:100101740 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB

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

MCM7 p.Glu9Asp Uncertain significance ★ ⚠ 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
AP4M1 p.Cys319Arg 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-ser9phe (accessed [today's date]).

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