Is AP1S3 p.Arg33Trp (c.97C>T) pathogenic?

AP1S3 p.Arg33Trp (c.97C>T) is classified Benign/Likely benign in AP1S3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-03-04). AlphaMissense: likely pathogenic (0.771); Low-frequency (popmax 1.13%, nfe); Associated with psoriasis 15, pustular, susceptibility to.

What condition is associated with AP1S3 p.Arg33Trp (c.97C>T)?

AP1S3 p.Arg33Trp (c.97C>T) is associated with psoriasis 15, pustular, susceptibility to (ClinVar).

How common is AP1S3 p.Arg33Trp (c.97C>T) in the general population?

AP1S3 p.Arg33Trp (c.97C>T) is low-frequency (popmax 1.13%, nfe) (gnomAD).

What do computational predictors say about AP1S3 p.Arg33Trp (c.97C>T)?

AlphaMissense predicts likely pathogenic (score 0.771) — an in-silico prediction, not a clinical call.

AP1S3 p.Arg33Trp

c.97C>T · rs138292988 · VCV160375

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.771 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.13%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

psoriasis 15, pustular, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.771	likely pathogenic
REVEL	0.313	indeterminate
SaProt	LLR -16.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	24.8	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 1.13% European (non-Finnish) · 13,357/1,179,974 alleles

Filtering AF 1.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.11%

Overall 0.961% 15,510/1,614,002 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.13%	88
Finnishnot grpmax-eligible	1.07%	93
Remaining individualsnot grpmax-eligible	0.947%	106
South Asian	0.418%	239
Admixed American	0.412%	243
Ashkenazi Jewishnot grpmax-eligible	0.372%	269
African / African-American	0.169%	591
Middle Eastern	0.132%	758
East Asian	0.00446%	22,433

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.Arg33Trp
Coding: c.97C>T
MANE Select: NM_001039569
dbSNP: rs138292988
Type: single nucleotide variant
Location: chr2:223777776 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 33: an α-helix; a UniProt-annotated variant site (risk factor for psors15; results in decreased tlr3 targeting to the endosomes indicating impaired function)

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.Ile83Thr Benign/Likely benign ★★ same condition
AP1S3 p.Phe4Cys Benign/Likely benign ★★ same condition
AP1S3 p.Thr22Ala 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
AP1S3 p.Gln74Lys 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-arg33trp (accessed [today's date]).

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