Is AP1S3 p.Val88Leu (c.262G>C) pathogenic?

AP1S3 p.Val88Leu (c.262G>C) is classified Uncertain significance in AP1S3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.9967); Ultra-rare (popmax 0.0176%, sas).

How common is AP1S3 p.Val88Leu (c.262G>C) in the general population?

AP1S3 p.Val88Leu (c.262G>C) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about AP1S3 p.Val88Leu (c.262G>C)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

AP1S3 p.Val88Leu

c.262G>C · VCV4641439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic · top 6% in AP1S3
REVEL	0.523	indeterminate
SaProt	LLR -14.77	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	27.0	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 0.0176% South Asian · 16/91,074 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00105% 17/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,692
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: AP1S3
Protein: p.Val88Leu
Coding: c.262G>C
MANE Select: NM_001039569
Type: single nucleotide variant
Location: chr2:223775930 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 88: an α-helix

Full AP1S3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1S3 p.Arg86Cys Uncertain significance ★★ ⚠ same type
AP1S3 p.Arg33Trp Benign/Likely benign ★★ same type
AP1S3 p.Ile83Thr Benign/Likely benign ★★ same type
AP1S3 p.Phe4Cys Benign/Likely benign ★★ same type
AP1S3 p.Thr22Ala Likely benign ★★ same type
AP1S3 p.Arg10Ter Uncertain significance ★ same type
AP1S3 p.Arg42Ser Uncertain significance ★ ⚠ same type
AP1S3 p.Asp115His 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/ap1s3-p-val88leu (accessed [today's date]).

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