Is AP1S3 p.Thr22Ala (c.64A>G) pathogenic?

AP1S3 p.Thr22Ala (c.64A>G) is classified Likely benign in AP1S3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0884); Rare (popmax 0.676%, mid); Associated with psoriasis 15, pustular, susceptibility to.

What condition is associated with AP1S3 p.Thr22Ala (c.64A>G)?

AP1S3 p.Thr22Ala (c.64A>G) is associated with psoriasis 15, pustular, susceptibility to (ClinVar).

How common is AP1S3 p.Thr22Ala (c.64A>G) in the general population?

AP1S3 p.Thr22Ala (c.64A>G) is rare (popmax 0.676%, mid) (gnomAD).

What do computational predictors say about AP1S3 p.Thr22Ala (c.64A>G)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

AP1S3 p.Thr22Ala

c.64A>G · rs149183052 · VCV1301564

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.676%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

psoriasis 15, pustular, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.74, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	16.45	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.676% Middle Eastern · 41/6,062 alleles

Filtering AF 0.512% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.455%

Overall 0.116% 1,874/1,613,880 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.676%	148
Ashkenazi Jewishnot grpmax-eligible	0.25%	400
Admixed American	0.213%	469
Remaining individualsnot grpmax-eligible	0.147%	679
European (non-Finnish)	0.126%	793
South Asian	0.0428%	2,335
African / African-American	0.016%	6,249
Finnishnot grpmax-eligible	0.00156%	63,986

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.Thr22Ala
Coding: c.64A>G
MANE Select: NM_001039569
dbSNP: rs149183052
Type: single nucleotide variant
Location: chr2:223777809 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 22: a UniProt-annotated variant site (in)

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

Disease context

psoriasis 15, pustular, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP1S3 p.Thr22Ser Likely benign ★ same residue
AP1S3 p.Arg33Trp Benign/Likely benign ★★ same condition
AP1S3 p.Ile83Thr Benign/Likely benign ★★ ⚠ same condition
AP1S3 p.Phe4Cys Benign/Likely benign ★★ same condition
AP1S3 p.Arg86Cys Uncertain significance ★★ ⚠ 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-thr22ala (accessed [today's date]).

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