Is AP1B1 p.Leu165Phe (c.493C>T) pathogenic?

AP1B1 p.Leu165Phe (c.493C>T) is classified Uncertain significance in AP1B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with AP1B1 p.Leu165Phe (c.493C>T)?

AP1B1 p.Leu165Phe (c.493C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP1B1 p.Leu165Phe (c.493C>T) in the general population?

AP1B1 p.Leu165Phe (c.493C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about AP1B1 p.Leu165Phe (c.493C>T)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

AP1B1 p.Leu165Phe

c.493C>T · VCV3403122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic
REVEL	0.481	indeterminate
SaProt	LLR -13.64	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 2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 18 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	25.6	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 0.00223% East Asian · 1/44,904 alleles

Overall 0.000124% 2/1,614,064 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,904
Admixed American	0.00167%	60,008

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: AP1B1
Protein: p.Leu165Phe
Coding: c.493C>T
MANE Select: NM_001127
Type: single nucleotide variant
Location: chr22:29358758 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB
Residue 165: an α-helix

Full AP1B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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AP1B1 p.Ala410Thr Uncertain significance ★ ⚠ same condition
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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/ap1b1-p-leu165phe (accessed [today's date]).

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