Is AP2S1 p.Arg42Gln (c.125G>A) pathogenic?

AP2S1 p.Arg42Gln (c.125G>A) is classified Uncertain significance in AP2S1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-07). AlphaMissense: likely pathogenic (0.9821); Absent from gnomAD v4.1.

How common is AP2S1 p.Arg42Gln (c.125G>A) in the general population?

AP2S1 p.Arg42Gln (c.125G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP2S1 p.Arg42Gln (c.125G>A)?

AlphaMissense predicts likely pathogenic (score 0.9821) — an in-silico prediction, not a clinical call.

AP2S1 p.Arg42Gln

c.125G>A · rs2122792210 · VCV1408296

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9821 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9821	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -14.57	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 5.7	GERP -1.8, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 12 kb · p 2.2e-20 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP2S1
Protein: p.Arg42Gln
Coding: c.125G>A
MANE Select: NM_004069
dbSNP: rs2122792210
Type: single nucleotide variant
Location: chr19:46846021 (GRCh38)
Gene constraint: LOEUF 0.478 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.03 · 1 PDB

Full AP2S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2S1 p.Arg42Gly Uncertain significance ★ ⚠ same residue
AP2S1 p.Arg15Cys Pathogenic ★★ same type
AP2S1 p.Arg15His Pathogenic/Likely pathogenic ★★ same type
AP2S1 p.Arg15Leu Pathogenic ★★ same type
AP2S1 c.153+5C>T Uncertain significance ★★ same type
AP2S1 p.Arg60His Uncertain significance ★★ ⚠ same type
AP2S1 p.Gln22His Uncertain significance ★★ ⚠ same type
AP2S1 p.Ile84Val 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/ap2s1-p-arg42gln (accessed [today's date]).

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