Is AP3S2 p.Ile5Val (c.13A>G) pathogenic?

AP3S2 p.Ile5Val (c.13A>G) is classified Uncertain significance in AP3S2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00139%, nfe).

How common is AP3S2 p.Ile5Val (c.13A>G) in the general population?

AP3S2 p.Ile5Val (c.13A>G) is very rare (popmax 0.00139%, nfe) (gnomAD).

What do computational predictors say about AP3S2 p.Ile5Val (c.13A>G)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

AP3S2 p.Ile5Val

c.13A>G · VCV4115552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00139%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 58 kb · p 0.79 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00139% European (non-Finnish) · 16/1,146,960 alleles

Filtering AF 0.000826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00103% 16/1,551,458 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: AP3S2
Protein: p.Ile5Val
Coding: c.13A>G
MANE Select: NM_005829
Type: single nucleotide variant
Location: chr15:89893937 (GRCh38)
Gene constraint: LOEUF 1.304 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.92

Full AP3S2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3S2 p.Ala143Val Uncertain significance ★ ⚠ same type
AP3S2 p.Ala157Val Uncertain significance ★ ⚠ same type
AP3S2 p.Ala69Val Uncertain significance ★ ⚠ same type
AP3S2 p.Arg175Gln Uncertain significance ★ ⚠ same type
AP3S2 p.Arg18His Uncertain significance ★ ⚠ same type
AP3S2 p.Arg33Gly Uncertain significance ★ ⚠ same type
AP3S2 p.Arg66Gln Uncertain significance ★ ⚠ same type
AP3S2 p.Asn178His 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/ap3s2-p-ile5val (accessed [today's date]).

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