Is AP1S1 c.182+252C>T pathogenic?

AP1S1 c.182+252C>T is classified Benign in AP1S1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-11-11). Common (popmax 53%, nfe) — too common for a highly-penetrant pathogenic allele.

AP1S1 c.182+252C>T

Q: How common is AP1S1 c.182+252C>T in the general population?

AP1S1 c.182+252C>T is common (popmax 53%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs35811390 · VCV1267114

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 53%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +252	deep intronic (+252 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -2
Non-coding constraint	Z 2.02	1 kb window · o/e 0.86 · regional · uncalibrated
Overall
CADD	0.808	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 53% European (non-Finnish) · 35,956/67,870 alleles

Filtering AF 52.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.3%

Overall 43.3% 65,521/151,434 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	61.7%	2
Ashkenazi Jewishnot grpmax-eligible	59.5%	2
European (non-Finnish)grpmax	53%	2
Admixed American	52.1%	2
Amishnot grpmax-eligible	49.9%	2
Middle Eastern	44.9%	2
Remaining individualsnot grpmax-eligible	41.8%	2
South Asian	34.1%	3
African / African-American	22.6%	4
East Asian	14.7%	7

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AP1S1
Coding: c.182+252C>T
MANE Select: NM_001283
dbSNP: rs35811390
Type: single nucleotide variant
Location: chr7:101157024 (GRCh38)
Gene constraint: LOEUF 1.078 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.83 · 1 PDB

Full AP1S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1S1 c.183-1G>C Pathogenic/Likely pathogenic ★★ same type
AP1S1 c.183-2A>G Pathogenic ★★ same type
AP1S1 c.291+2T>A Pathogenic/Likely pathogenic ★★ same type
AP1S1 p.Gln74Ter Pathogenic/Likely pathogenic ★★ same type
AP1S1 p.Tyr62Ter Pathogenic/Likely pathogenic ★★ same type
AP1S1 c.182+78T>C Benign ★★ same type
AP1S1 c.183-17T>C Likely benign ★★ same type
AP1S1 c.183-23G>A Benign ★★ 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/ap1s1-c-182-plus-252c-t (accessed [today's date]).

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