Is AP4E1 p.Pro717Ser (c.2149C>T) pathogenic?

AP4E1 p.Pro717Ser (c.2149C>T) is classified Uncertain significance in AP4E1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1357); Ultra-rare (popmax 0.0173%, afr); Associated with Spastic paraplegia.

What condition is associated with AP4E1 p.Pro717Ser (c.2149C>T)?

AP4E1 p.Pro717Ser (c.2149C>T) is associated with Spastic paraplegia, stuttering, familial persistent, 1, hereditary spastic paraplegia 51 (ClinVar).

How common is AP4E1 p.Pro717Ser (c.2149C>T) in the general population?

AP4E1 p.Pro717Ser (c.2149C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about AP4E1 p.Pro717Ser (c.2149C>T)?

AlphaMissense predicts likely benign (score 0.1357) — an in-silico prediction, not a clinical call.

AP4E1 p.Pro717Ser

c.2149C>T · rs150743968 · VCV458249

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1357 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1357	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0173% African / African-American · 13/75,028 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00248% 40/1,613,900 alleles · ultra-rare exomes 29/1,461,654 · genomes 11/152,246 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,771
Remaining individualsnot grpmax-eligible	0.0048%	20,833
European (non-Finnish)	0.00203%	49,164

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.Pro717Ser
Coding: c.2149C>T
MANE Select: NM_007347
dbSNP: rs150743968
Type: single nucleotide variant
Location: chr15:50993428 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB

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: stuttering, familial persistent, 1 hereditary spastic paraplegia 51

Similar variants

AP4E1 p.Arg1105Ter Pathogenic ★★ same condition
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

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-pro717ser (accessed [today's date]).

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