Is AP3S2 p.Ala157Val (c.470C>T) pathogenic?

AP3S2 p.Ala157Val (c.470C>T) is classified Uncertain significance in AP3S2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: ambiguous (0.3886); Very rare (popmax 0.000678%, nfe).

How common is AP3S2 p.Ala157Val (c.470C>T) in the general population?

AP3S2 p.Ala157Val (c.470C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about AP3S2 p.Ala157Val (c.470C>T)?

AlphaMissense predicts ambiguous (score 0.3886) — an in-silico prediction, not a clinical call.

AP3S2 p.Ala157Val

c.470C>T · rs1178963766 · VCV3127540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3886	ambiguous
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 6.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 58 kb · p 0.79 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,872 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,612,974 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.Ala157Val
Coding: c.470C>T
MANE Select: NM_005829
dbSNP: rs1178963766
Type: single nucleotide variant
Location: chr15:89835627 (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.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
AP3S2 p.Asp60Glu 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-ala157val (accessed [today's date]).

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