Is AP1S3 p.Thr80= (c.240G>A) pathogenic?

AP1S3 p.Thr80= (c.240G>A) is classified Likely benign in AP1S3 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-02-27). Ultra-rare (popmax 0.0302%, nfe).

How common is AP1S3 p.Thr80= (c.240G>A) in the general population?

AP1S3 p.Thr80= (c.240G>A) is ultra-rare (popmax 0.0302%, nfe) (gnomAD).

AP1S3 p.Thr80=

c.240G>A · rs200314987 · VCV3050716

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0302%, 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 -3.7	GERP -1.8
Overall
CADD	3.213	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0302% European (non-Finnish) · 356/1,180,002 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0266%

Overall 0.0243% 392/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)grpmax	0.0302%	3,315
African / African-American	0.0107%	9,380
Admixed American	0.005%	20,007
Finnishnot grpmax-eligible	0.00469%	21,343
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,878

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: AP1S3
Protein: p.Thr80=
Coding: c.240G>A
MANE Select: NM_001039569
dbSNP: rs200314987
Type: single nucleotide variant
Location: chr2:223775952 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 80: an α-helix

Full AP1S3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1S3 p.Arg86Cys Uncertain significance ★★ ⚠ same type
AP1S3 p.Arg33Trp Benign/Likely benign ★★ same type
AP1S3 p.Ile83Thr Benign/Likely benign ★★ ⚠ same type
AP1S3 p.Phe4Cys Benign/Likely benign ★★ same type
AP1S3 p.Thr22Ala Likely benign ★★ same type
AP1S3 p.Arg10Ter Uncertain significance ★ same type
AP1S3 p.Arg42Ser Uncertain significance ★ ⚠ same type
AP1S3 p.Asp115His 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/ap1s3-p-thr80 (accessed [today's date]).

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