Is AP1S3 p.Phe4Cys (c.11T>G) pathogenic?

AP1S3 p.Phe4Cys (c.11T>G) is classified Benign/Likely benign in AP1S3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.7859); Low-frequency (popmax 1.34%, nfe); Associated with psoriasis 15, pustular, susceptibility to.

What condition is associated with AP1S3 p.Phe4Cys (c.11T>G)?

AP1S3 p.Phe4Cys (c.11T>G) is associated with psoriasis 15, pustular, susceptibility to (ClinVar).

How common is AP1S3 p.Phe4Cys (c.11T>G) in the general population?

AP1S3 p.Phe4Cys (c.11T>G) is low-frequency (popmax 1.34%, nfe) (gnomAD).

What do computational predictors say about AP1S3 p.Phe4Cys (c.11T>G)?

AlphaMissense predicts likely pathogenic (score 0.7859) — an in-silico prediction, not a clinical call.

AP1S3 p.Phe4Cys

c.11T>G · rs116107386 · VCV160376

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7859 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.34%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

psoriasis 15, pustular, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.7859	likely pathogenic
REVEL	0.619	indeterminate
SaProt	LLR -11.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	28.4	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 1.34% European (non-Finnish) · 15,859/1,179,680 alleles

Filtering AF 1.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.32%

Overall 1.08% 17,504/1,613,370 alleles · low-frequency exomes 16,188/1,461,064 · genomes 1,316/152,306 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.08%	48
European (non-Finnish)grpmax	1.34%	74
Remaining individualsnot grpmax-eligible	0.797%	125
Admixed American	0.594%	168
Finnishnot grpmax-eligible	0.452%	221
Ashkenazi Jewishnot grpmax-eligible	0.436%	229
Middle Eastern	0.396%	252
African / African-American	0.224%	447
South Asian	0.176%	568
East Asian	0.00446%	22,423

Amish 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.Phe4Cys
Coding: c.11T>G
MANE Select: NM_001039569
dbSNP: rs116107386
Type: single nucleotide variant
Location: chr2:223777862 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 4: a β-strand; a UniProt-annotated variant site (risk factor for psors15; results in decreased protein levels)

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.Arg33Trp Benign/Likely benign ★★ same condition
AP1S3 p.Ile83Thr 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-phe4cys (accessed [today's date]).

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