Is AP1S3 p.Ile83Thr (c.248T>C) pathogenic?

AP1S3 p.Ile83Thr (c.248T>C) is classified Benign/Likely benign in AP1S3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.1511); Low-frequency (popmax 1.04%, sas); Associated with psoriasis 15, pustular, susceptibility to.

What condition is associated with AP1S3 p.Ile83Thr (c.248T>C)?

AP1S3 p.Ile83Thr (c.248T>C) is associated with psoriasis 15, pustular, susceptibility to (ClinVar).

How common is AP1S3 p.Ile83Thr (c.248T>C) in the general population?

AP1S3 p.Ile83Thr (c.248T>C) is low-frequency (popmax 1.04%, sas) (gnomAD).

What do computational predictors say about AP1S3 p.Ile83Thr (c.248T>C)?

AlphaMissense predicts likely benign (score 0.1511) — an in-silico prediction, not a clinical call.

AP1S3 p.Ile83Thr

c.248T>C · rs202157374 · VCV1301563

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1511 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

psoriasis 15, pustular, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1511	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -9.41	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 5.4	GERP 0.68, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	20.8	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 1.04% South Asian · 945/91,080 alleles

Filtering AF 0.983% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.961%

Overall 0.0614% 991/1,614,180 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.04%	96
Remaining individualsnot grpmax-eligible	0.0608%	1,645
Middle Eastern	0.0165%	6,062
African / African-American	0.004%	25,018
East Asian	0.00223%	44,884
Admixed American	0.00167%	60,022
European (non-Finnish)	0.000169%	590,005

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.Ile83Thr
Coding: c.248T>C
MANE Select: NM_001039569
dbSNP: rs202157374
Type: single nucleotide variant
Location: chr2:223775944 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 83: a UniProt-annotated variant site (in); an α-helix

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.Ile83Met Uncertain significance ★ ⚠ same residue
AP1S3 p.Arg33Trp 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

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-ile83thr (accessed [today's date]).

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