Is AP1S3 p.Asp115His (c.343G>C) pathogenic?

AP1S3 p.Asp115His (c.343G>C) is classified Uncertain significance in AP1S3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9841); Absent from gnomAD v4.1.

How common is AP1S3 p.Asp115His (c.343G>C) in the general population?

AP1S3 p.Asp115His (c.343G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP1S3 p.Asp115His (c.343G>C)?

AlphaMissense predicts likely pathogenic (score 0.9841) — an in-silico prediction, not a clinical call.

AP1S3 p.Asp115His

c.343G>C · VCV4641440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9841 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9841	likely pathogenic
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -14.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 79 kb · p 0.028 · regional, not allelic
Overall
CADD	29.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP1S3
Protein: p.Asp115His
Coding: c.343G>C
MANE Select: NM_001039569
Type: single nucleotide variant
Location: chr2:223765299 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 93.61 · 20 PDB
Residue 115: 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.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-asp115his (accessed [today's date]).

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