Is AP2S1 p.Ile32= (c.96C>T) pathogenic?

AP2S1 p.Ile32= (c.96C>T) is classified Likely benign in AP2S1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). Very rare (popmax 0.00186%, nfe).

How common is AP2S1 p.Ile32= (c.96C>T) in the general population?

AP2S1 p.Ile32= (c.96C>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

AP2S1 p.Ile32=

c.96C>T · rs376074817 · VCV2886716

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -3
Overall
CADD	6.537	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00186% European (non-Finnish) · 22/1,180,030 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00167% 27/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)grpmax	0.00186%	53,638
Finnishnot grpmax-eligible	0.00156%	64,028
African / African-American	0.00134%	74,904

Remaining individuals 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: AP2S1
Protein: p.Ile32=
Coding: c.96C>T
MANE Select: NM_004069
dbSNP: rs376074817
Type: single nucleotide variant
Location: chr19:46846050 (GRCh38)
Gene constraint: LOEUF 0.478 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.03 · 1 PDB
Residue 32: an α-helix

Full AP2S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2S1 p.Arg15Cys Pathogenic ★★ same type
AP2S1 p.Arg15His Pathogenic/Likely pathogenic ★★ same type
AP2S1 p.Arg15Leu Pathogenic ★★ same type
AP2S1 c.153+5C>T Uncertain significance ★★ same type
AP2S1 p.Arg60His Uncertain significance ★★ ⚠ same type
AP2S1 p.Gln22His Uncertain significance ★★ ⚠ same type
AP2S1 p.Ile84Val Uncertain significance ★★ ⚠ same type
AP2S1 p.Thr112Met 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/ap2s1-p-ile32 (accessed [today's date]).

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