Is AP1S1 p.Arg28Gln (c.83G>A) pathogenic?

AP1S1 p.Arg28Gln (c.83G>A) is classified Uncertain significance in AP1S1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.2798); Very rare (popmax 0.000763%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP1S1 p.Arg28Gln (c.83G>A)?

AP1S1 p.Arg28Gln (c.83G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP1S1 p.Arg28Gln (c.83G>A) in the general population?

AP1S1 p.Arg28Gln (c.83G>A) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about AP1S1 p.Arg28Gln (c.83G>A)?

AlphaMissense predicts likely benign (score 0.2798) — an in-silico prediction, not a clinical call.

AP1S1 p.Arg28Gln

c.83G>A · VCV4114689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2798	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.88, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 6,048 bp · p 2.2e-08 · regional, not allelic
Overall
CADD	24.6	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 0.000763% European (non-Finnish) · 9/1,178,998 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,611,484 alleles · very rare

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: AP1S1
Protein: p.Arg28Gln
Coding: c.83G>A
MANE Select: NM_001283
Type: single nucleotide variant
Location: chr7:101156673 (GRCh38)
Gene constraint: LOEUF 1.078 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.83 · 1 PDB
Residue 28: an α-helix

Full AP1S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP1S1 p.Leu6= Likely benign ★★ same condition
AP1S1 c.183-5C>T Conflicting classifications of pathogenicity ★ same condition
AP1S1 p.Arg10Trp Uncertain significance ★ ⚠ same condition
AP1S1 p.Arg3Trp Uncertain significance ★ same condition
AP1S1 p.Asp122Ala Uncertain significance ★ ⚠ same condition
AP1S1 p.Asp122Asn Uncertain significance ★ ⚠ same condition
AP1S1 p.Asp54Gly Uncertain significance ★ same condition
AP1S1 p.Glu51Lys Uncertain significance ★ ⚠ same condition

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/ap1s1-p-arg28gln (accessed [today's date]).

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