Is AP4E1 p.Trp446Arg (c.1336T>C) pathogenic?

AP4E1 p.Trp446Arg (c.1336T>C) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-12-12). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 0.00666%, amr); Associated with hereditary spastic paraplegia.

What condition is associated with AP4E1 p.Trp446Arg (c.1336T>C)?

AP4E1 p.Trp446Arg (c.1336T>C) is associated with hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Trp446Arg (c.1336T>C) in the general population?

AP4E1 p.Trp446Arg (c.1336T>C) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about AP4E1 p.Trp446Arg (c.1336T>C)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

AP4E1 p.Trp446Arg

c.1336T>C · rs190643886 · VCV1343980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic · top 1% in AP4E1
REVEL	0.739	pathogenic-leaning
SaProt	LLR -12.75	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 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	29.8	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 0.00666% Admixed American · 4/60,030 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000558% 9/1,613,120 alleles · very rare exomes 5/1,460,786 · genomes 4/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,008
Remaining individualsnot grpmax-eligible	0.0016%	62,466
African / African-American	0.00133%	75,026
European (non-Finnish)	0.000254%	393,077

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.Trp446Arg
Coding: c.1336T>C
MANE Select: NM_007347
dbSNP: rs190643886
Type: single nucleotide variant
Location: chr15:50949845 (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

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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-trp446arg (accessed [today's date]).

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