Is AP1B1 p.Arg108Trp (c.322C>T) pathogenic?

AP1B1 p.Arg108Trp (c.322C>T) is classified Pathogenic in AP1B1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-08-08). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.0011%, sas); Associated with ichthyosiform erythroderma, corneal involvement, and hearing loss.

What condition is associated with AP1B1 p.Arg108Trp (c.322C>T)?

AP1B1 p.Arg108Trp (c.322C>T) is associated with ichthyosiform erythroderma, corneal involvement, and hearing loss (ClinVar).

How common is AP1B1 p.Arg108Trp (c.322C>T) in the general population?

AP1B1 p.Arg108Trp (c.322C>T) is very rare (popmax 0.0011%, sas) (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.Arg108Trp (c.322C>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

AP1B1 p.Arg108Trp

c.322C>T · rs1160266009 · VCV1700245

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ichthyosiform erythroderma, corneal involvement, and hearing loss

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 6% in AP1B1
REVEL	0.552	indeterminate
SaProt	LLR -14.78	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 2.5	GERP -3, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 18 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	29.2	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

Grpmax group 0.0011% South Asian · 1/90,658 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,611,806 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,658
European (non-Finnish)	0.000339%	294,819

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.Arg108Trp
Coding: c.322C>T
MANE Select: NM_001127
dbSNP: rs1160266009
Type: single nucleotide variant
Location: chr22:29358929 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB
Residue 108: 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.Ala783= Benign ★★ same condition
AP1B1 p.Leu68= Benign ★★ same condition
AP1B1 p.Met1Thr Likely pathogenic ★ same condition
AP1B1 p.Leu223Pro Uncertain significance ★ ⚠ same condition
AP1B1 p.Val176= Uncertain significance ★ same condition
AP1B1 c.38-1G>A Pathogenic same condition
AP1B1 p.Cys144Arg Pathogenic same condition
AP1B1 p.Gln618Ter 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-arg108trp (accessed [today's date]).

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