Is AP2S1 p.Arg61His (c.182G>A) pathogenic?

AP2S1 p.Arg61His (c.182G>A) is classified Uncertain significance in AP2S1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely pathogenic (0.9547); Very rare (popmax 8.47e-05%, nfe).

How common is AP2S1 p.Arg61His (c.182G>A) in the general population?

AP2S1 p.Arg61His (c.182G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AP2S1 p.Arg61His (c.182G>A)?

AlphaMissense predicts likely pathogenic (score 0.9547) — an in-silico prediction, not a clinical call.

AP2S1 p.Arg61His

c.182G>A · rs754997253 · VCV2502631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9547	likely pathogenic
REVEL	0.447	indeterminate
SaProt	LLR -13.14	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 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 12 kb · p 2.2e-20 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.84e-05% 1/1,461,870 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: AP2S1
Protein: p.Arg61His
Coding: c.182G>A
MANE Select: NM_004069
dbSNP: rs754997253
Type: single nucleotide variant
Location: chr19:46839550 (GRCh38)
Gene constraint: LOEUF 0.478 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.03 · 1 PDB
Residue 61: a β-strand

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

Similar variants

AP2S1 p.Arg61Cys 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-arg61his (accessed [today's date]).

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