Is AP4S1 p.Arg97Ter (c.289C>T) pathogenic?

AP4S1 p.Arg97Ter (c.289C>T) is classified Pathogenic/Likely pathogenic in AP4S1 (ClinVar, Multiple submitters, 26 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0312%, eas); Associated with Spastic paraplegia.

What condition is associated with AP4S1 p.Arg97Ter (c.289C>T)?

AP4S1 p.Arg97Ter (c.289C>T) is associated with Spastic paraplegia, intellectual disability, hereditary spastic paraplegia 52 (ClinVar).

How common is AP4S1 p.Arg97Ter (c.289C>T) in the general population?

AP4S1 p.Arg97Ter (c.289C>T) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

AP4S1 p.Arg97Ter

c.289C>T · rs200440467 · VCV234924

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 26 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1.5, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,844 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0115% 186/1,613,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,203
South Asian	0.0176%	5,691
Admixed American	0.0167%	6,001
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)	0.0109%	9,144
African / African-American	0.008%	12,496
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Finnishnot grpmax-eligible	0.00156%	63,978

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: AP4S1
Protein: p.Arg97Ter
Coding: c.289C>T
MANE Select: NM_001128126
dbSNP: rs200440467
Type: single nucleotide variant
Location: chr14:31072968 (GRCh38)
Gene constraint: LOEUF 1.675 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 4 PDB

Full AP4S1 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: intellectual disability hereditary spastic paraplegia 52

Similar variants

AP4S1 p.Arg97Leu Uncertain significance ★ ⚠ same residue
AP4S1 p.Arg97Gln Uncertain significance ★★ ⚠ same residue
AP4S1 c.139-2A>G Likely pathogenic ★★ same condition
AP4S1 c.294+1G>T Pathogenic/Likely pathogenic ★★ same condition
AP4S1 c.295-3C>A Pathogenic/Likely pathogenic ★★ same condition
AP4S1 p.Arg15Ter Pathogenic ★★ same condition
AP4S1 p.Arg42Ter Pathogenic ★★ same condition
AP4S1 p.Met1Thr Likely pathogenic ★★ 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/ap4s1-p-arg97ter (accessed [today's date]).

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