Is AP1S3 p.Arg86Cys (c.256C>T) pathogenic?

AP1S3 p.Arg86Cys (c.256C>T) is classified Uncertain significance in AP1S3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.671); Ultra-rare (popmax 0.0164%, mid).

How common is AP1S3 p.Arg86Cys (c.256C>T) in the general population?

AP1S3 p.Arg86Cys (c.256C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about AP1S3 p.Arg86Cys (c.256C>T)?

AlphaMissense predicts likely pathogenic (score 0.671) — an in-silico prediction, not a clinical call.

AP1S3 p.Arg86Cys

c.256C>T · VCV3403517

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.671	likely pathogenic
REVEL	0.39	indeterminate
SaProt	LLR -12.87	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	33.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000805% 13/1,613,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00329%	30,359
Admixed American	0.00167%	59,994
European (non-Finnish)	0.000678%	147,500

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.Arg86Cys
Coding: c.256C>T
MANE Select: NM_001039569
Type: single nucleotide variant
Location: chr2:223775936 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 86: an α-helix

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

Similar variants

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
AP1S3 p.Gln74Lys 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-arg86cys (accessed [today's date]).

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