Is AP1S2 p.Arg52Ter (c.154C>T) pathogenic?

AP1S2 p.Arg52Ter (c.154C>T) is classified Pathogenic in AP1S2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-16). Absent from gnomAD v4.1; Associated with AP1S2-related disorder.

What condition is associated with AP1S2 p.Arg52Ter (c.154C>T)?

AP1S2 p.Arg52Ter (c.154C>T) is associated with AP1S2-related disorder, syndromic X-linked intellectual disability 5 (ClinVar).

How common is AP1S2 p.Arg52Ter (c.154C>T) in the general population?

AP1S2 p.Arg52Ter (c.154C>T) is absent from gnomAD v4.1 (gnomAD).

AP1S2 p.Arg52Ter

c.154C>T · rs104894735 · VCV10778

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

AP1S2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 6
REVEL	0.136	moderately benign-leaning
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Pangolin	Δ0.38	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.7	GERP -0.069, 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

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: AP1S2
Protein: p.Arg52Ter
Coding: c.154C>T
MANE Select: NM_001272071
dbSNP: rs104894735
Type: single nucleotide variant
Location: chrX:15852371 (GRCh38)
Structure: AlphaFold pLDDT 94.36

Full AP1S2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AP1S2-related disorder

Also linked: syndromic X-linked intellectual disability 5

Similar variants

AP1S2 c.-1+1G>A Pathogenic/Likely pathogenic ★★ same condition
AP1S2 p.Gln123Ter Pathogenic ★★ same condition
AP1S2 c.1-3C>A Pathogenic ★ same condition
AP1S2 c.288+1G>A Pathogenic ★ same condition
AP1S2 c.288+5G>A Likely pathogenic ★ same condition
AP1S2 c.426+1G>T Pathogenic ★ same condition
AP1S2 p.Arg14Ter Pathogenic ★ same condition
AP1S2 c.179+3A>G Conflicting classifications of pathogenicity ★ 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/ap1s2-p-arg52ter (accessed [today's date]).

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