Is AP1S3 p.Arg10Ter (c.28C>T) pathogenic?

AP1S3 p.Arg10Ter (c.28C>T) is classified Uncertain significance in AP1S3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-23). Ultra-rare (popmax 0.0117%, amr).

How common is AP1S3 p.Arg10Ter (c.28C>T) in the general population?

AP1S3 p.Arg10Ter (c.28C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

AP1S3 p.Arg10Ter

c.28C>T · rs1372202707 · VCV2688582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.95, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,928 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00186% 30/1,613,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,561
European (non-Finnish)	0.00195%	51,301

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.Arg10Ter
Coding: c.28C>T
MANE Select: NM_001039569
dbSNP: rs1372202707
Type: single nucleotide variant
Location: chr2:223777845 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB

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

Similar variants

AP1S3 p.Arg86Cys Uncertain significance ★★ ⚠ same type
AP1S3 p.Arg33Trp Benign/Likely benign ★★ same type
AP1S3 p.Ile83Thr Benign/Likely benign ★★ same type
AP1S3 p.Phe4Cys Benign/Likely benign ★★ same type
AP1S3 p.Thr22Ala Likely benign ★★ 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-arg10ter (accessed [today's date]).

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