Is AP1S2 p.Leu15Arg (c.44T>G) pathogenic?

AP1S2 p.Leu15Arg (c.44T>G) is classified Uncertain significance in AP1S2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-30). AlphaMissense: likely pathogenic (0.9946); Absent from gnomAD v4.1.

How common is AP1S2 p.Leu15Arg (c.44T>G) in the general population?

AP1S2 p.Leu15Arg (c.44T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP1S2 p.Leu15Arg (c.44T>G)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

AP1S2 p.Leu15Arg

c.44T>G · rs2147328169 · VCV1302899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -14.20	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 6,547 bp · p 4.2e-08 · regional, not allelic
Overall
CADD	29.4	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

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.Leu15Arg
Coding: c.44T>G
MANE Select: NM_001272071
dbSNP: rs2147328169
Type: single nucleotide variant
Location: chrX:15852481 (GRCh38)
Structure: AlphaFold pLDDT 94.36

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

Similar variants

AP1S2 p.Leu15= Likely benign ★ same residue
AP1S2 c.-1+1G>A Pathogenic/Likely pathogenic ★★ same type
AP1S2 p.Arg52Ter Pathogenic ★★ same type
AP1S2 p.Gln123Ter Pathogenic ★★ same type
AP1S2 p.Asn129Thr Uncertain significance ★★ ⚠ same type
AP1S2 p.Gly158Arg Uncertain significance ★★ ⚠ same type
AP1S2 p.Ile134Thr Uncertain significance ★★ ⚠ same type
AP1S2 p.Ile82Val Uncertain significance ★★ ⚠ same type

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-leu15arg (accessed [today's date]).

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