Is AP1S2 p.Gly158Arg (c.472G>A) pathogenic?

AP1S2 p.Gly158Arg (c.472G>A) is classified Uncertain significance in AP1S2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.9268); Very rare (popmax 0.00179%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP1S2 p.Gly158Arg (c.472G>A)?

AP1S2 p.Gly158Arg (c.472G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP1S2 p.Gly158Arg (c.472G>A) in the general population?

AP1S2 p.Gly158Arg (c.472G>A) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about AP1S2 p.Gly158Arg (c.472G>A)?

AlphaMissense predicts likely pathogenic (score 0.9268) — an in-silico prediction, not a clinical call.

AP1S2 p.Gly158Arg

c.472G>A · rs143031717 · VCV1039029

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9268 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9268	likely pathogenic
REVEL	0.28	benign-leaning
SaProt	LLR -11.49	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.40	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 18 kb · p 0.042 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G155R vs ClinVar G158R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00179% European (non-Finnish) · 16/892,509 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000859%

Overall 0.00141% 17/1,207,008 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,513
European (non-Finnish)grpmax	0.00179%	55,782

Remaining individuals 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: AP1S2
Protein: p.Gly158Arg
Coding: c.472G>A
MANE Select: NM_001272071
dbSNP: rs143031717
Type: single nucleotide variant
Location: chrX:15827336 (GRCh38)
Structure: AlphaFold pLDDT 94.36

Full AP1S2 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

AP1S2 p.Gly158Glu Uncertain significance ★ ⚠ same residue
AP1S2 p.Ile134Thr Uncertain significance ★★ ⚠ same condition
AP1S2 p.Ile82Val Uncertain significance ★★ ⚠ same condition
AP1S2 p.Leu54Val Uncertain significance ★★ ⚠ same condition
AP1S2 c.289-8C>T Benign/Likely benign ★★ same condition
AP1S2 p.Ser96= Benign/Likely benign ★★ same condition
AP1S2 p.Val38Ile Benign/Likely benign ★★ ⚠ same condition
AP1S2 p.Ser23Ter Pathogenic ★ 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/ap1s2-p-gly158arg (accessed [today's date]).

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