Is AP3M1 p.Leu269Pro (c.806T>C) pathogenic?

AP3M1 p.Leu269Pro (c.806T>C) is classified Uncertain significance in AP3M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.5865); Absent from gnomAD v4.1.

How common is AP3M1 p.Leu269Pro (c.806T>C) in the general population?

AP3M1 p.Leu269Pro (c.806T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP3M1 p.Leu269Pro (c.806T>C)?

AlphaMissense predicts likely pathogenic (score 0.5865) — an in-silico prediction, not a clinical call.

AP3M1 p.Leu269Pro

c.806T>C · VCV4115464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5865 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5865	likely pathogenic
REVEL	0.225	benign-leaning
SaProt	LLR -4.00	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 15 kb · p 3e-05 · regional, not allelic
Overall
CADD	23.3	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

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: AP3M1
Protein: p.Leu269Pro
Coding: c.806T>C
MANE Select: NM_012095
Type: single nucleotide variant
Location: chr10:74126353 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.18 · 5 PDB
Residue 269: the mhd domain

Full AP3M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3M1 p.Leu269Arg Uncertain significance ★ ⚠ same residue
AP3M1 p.Ala40Val Uncertain significance ★ ⚠ same type
AP3M1 p.Arg168Cys Uncertain significance ★ ⚠ same type
AP3M1 p.Arg169Gln Uncertain significance ★ ⚠ same type
AP3M1 p.Arg241Cys Uncertain significance ★ ⚠ same type
AP3M1 p.Arg241His Uncertain significance ★ ⚠ same type
AP3M1 p.Arg391Cys Uncertain significance ★ ⚠ same type
AP3M1 p.Arg61Gln 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/ap3m1-p-leu269pro (accessed [today's date]).

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