Is AP4E1 p.Ser1117= (c.3351C>T) pathogenic?

AP4E1 p.Ser1117= (c.3351C>T) is classified Conflicting classifications of pathogenicity in AP4E1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0866%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Ser1117= (c.3351C>T)?

AP4E1 p.Ser1117= (c.3351C>T) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Ser1117= (c.3351C>T) in the general population?

AP4E1 p.Ser1117= (c.3351C>T) is ultra-rare (popmax 0.0866%, afr) (gnomAD).

AP4E1 p.Ser1117=

c.3351C>T · rs371690344 · VCV698049

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0866%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.6	GERP -3.4
Overall
CADD	5.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0866% African / African-American · 65/75,052 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0635%

Overall 0.00409% 66/1,614,168 alleles · ultra-rare exomes 24/1,461,844 · genomes 42/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0866%	1,155
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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: AP4E1
Protein: p.Ser1117=
Coding: c.3351C>T
MANE Select: NM_007347
dbSNP: rs371690344
Type: single nucleotide variant
Location: chr15:51002599 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 1117: the 'interaction with tepsin' region

Full AP4E1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: hereditary spastic paraplegia

Similar variants

AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Ala119Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala45Thr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala475Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Arg646Cys Uncertain significance ★★ same condition
AP4E1 p.Asn1086Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asn311Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp484Val 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/ap4e1-p-ser1117 (accessed [today's date]).

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