Is AP1B1 p.Leu223Pro (c.668T>C) pathogenic?

AP1B1 p.Leu223Pro (c.668T>C) is classified Uncertain significance in AP1B1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-29). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with ichthyosiform erythroderma, corneal involvement, and hearing loss.

What condition is associated with AP1B1 p.Leu223Pro (c.668T>C)?

AP1B1 p.Leu223Pro (c.668T>C) is associated with ichthyosiform erythroderma, corneal involvement, and hearing loss (ClinVar).

How common is AP1B1 p.Leu223Pro (c.668T>C) in the general population?

AP1B1 p.Leu223Pro (c.668T>C) is absent from gnomAD v4.1 (gnomAD).

How is KID syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AP1B1 p.Leu223Pro (c.668T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

AP1B1 p.Leu223Pro

c.668T>C · rs2147995205 · VCV1700246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ichthyosiform erythroderma, corneal involvement, and hearing loss

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 6% in AP1B1
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -14.85	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 18 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	32.0	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

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: AP1B1
Protein: p.Leu223Pro
Coding: c.668T>C
MANE Select: NM_001127
dbSNP: rs2147995205
Type: single nucleotide variant
Location: chr22:29356474 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB
Residue 223: an α-helix

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

Disease context

ichthyosiform erythroderma, corneal involvement, and hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For KID syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Neonatal

Similar variants

AP1B1 p.Leu223fs Pathogenic same residue
AP1B1 p.Ala783= Benign ★★ same condition
AP1B1 p.Leu68= Benign ★★ same condition
AP1B1 p.Met1Thr Likely pathogenic ★ same condition
AP1B1 p.Val176= Uncertain significance ★ same condition
AP1B1 c.38-1G>A Pathogenic same condition
AP1B1 p.Arg108Trp Pathogenic same condition
AP1B1 p.Cys144Arg Pathogenic same condition

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-leu223pro (accessed [today's date]).

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