Is AP4E1 p.Pro731= (c.2193T>C) pathogenic?

AP4E1 p.Pro731= (c.2193T>C) is classified Likely benign in AP4E1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-11). Ultra-rare (popmax 0.0267%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Pro731= (c.2193T>C)?

AP4E1 p.Pro731= (c.2193T>C) is associated with Spastic paraplegia (ClinVar).

How common is AP4E1 p.Pro731= (c.2193T>C) in the general population?

AP4E1 p.Pro731= (c.2193T>C) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

AP4E1 p.Pro731=

c.2193T>C · rs201935060 · VCV1079523

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.6, phastCons 0.98
Overall
CADD	6.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% African / African-American · 20/75,046 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00341% 55/1,614,012 alleles · ultra-rare exomes 52/1,461,718 · genomes 3/152,294 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0777%	1,287
African / African-Americangrpmax	0.0267%	3,752
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0144%	6,945
European (non-Finnish)	0.000169%	589,988

Ashkenazi Jewish 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: AP4E1
Protein: p.Pro731=
Coding: c.2193T>C
MANE Select: NM_007347
dbSNP: rs201935060
Type: single nucleotide variant
Location: chr15:50993472 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 731: 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

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.Asp484Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp938Gly 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-pro731 (accessed [today's date]).

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