Is AP4E1 p.Ser681= (c.2043T>C) pathogenic?

AP4E1 p.Ser681= (c.2043T>C) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-24). Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia.

What condition is associated with AP4E1 p.Ser681= (c.2043T>C)?

AP4E1 p.Ser681= (c.2043T>C) is associated with hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Ser681= (c.2043T>C) in the general population?

AP4E1 p.Ser681= (c.2043T>C) is absent from gnomAD v4.1 (gnomAD).

AP4E1 p.Ser681=

c.2043T>C · rs2140914739 · VCV1343997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary 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 0.91	GERP 1.3, phastCons 1
Overall
CADD	7.608	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP4E1
Protein: p.Ser681=
Coding: c.2043T>C
MANE Select: NM_007347
dbSNP: rs2140914739
Type: single nucleotide variant
Location: chr15:50984098 (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

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

Similar variants

AP4E1 p.Asn311Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln1093Glu Uncertain significance ★★ ⚠ same condition
AP4E1 p.Thr369Pro Uncertain significance ★★ ⚠ same condition
AP4E1 p.Thr71Ile Uncertain significance ★★ ⚠ same condition
AP4E1 p.Tyr1125Cys Uncertain significance ★★ ⚠ same condition
AP4E1 c.1177-9T>C Benign/Likely benign ★★ same condition
AP4E1 c.2905-8A>G Benign ★★ same condition
AP4E1 p.Asn428Ser Benign/Likely benign ★★ 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-ser681 (accessed [today's date]).

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