Is ABCA12 p.Phe2286fs (c.6858del) pathogenic?

ABCA12 p.Phe2286fs (c.6858del) is classified Pathogenic in ABCA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.0112%, eas); Associated with autosomal recessive congenital ichthyosis 4A.

What condition is associated with ABCA12 p.Phe2286fs (c.6858del)?

ABCA12 p.Phe2286fs (c.6858del) is associated with autosomal recessive congenital ichthyosis 4A, autosomal recessive congenital ichthyosis 4B (ClinVar).

How common is ABCA12 p.Phe2286fs (c.6858del) in the general population?

ABCA12 p.Phe2286fs (c.6858del) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

How is Lamellar ichthyosis inherited?

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

ABCA12 p.Phe2286fs

c.6858del · rs751949857 · VCV2734375

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

autosomal recessive congenital ichthyosis 4A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 46 of 53
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,800 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00031% 5/1,612,464 alleles · ultra-rare

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: ABCA12
Protein: p.Phe2286fs
Coding: c.6858del
MANE Select: NM_173076
dbSNP: rs751949857
Type: Deletion
Location: chr2:214949144 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32
Residue 2286: the abc transporter 2 domain; a UniProt-annotated variant site (in arci4b); a UniProt-annotated variant site (in arci4b; uncertain significance)

Full ABCA12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive congenital ichthyosis 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive congenital ichthyosis 4B

For Lamellar ichthyosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ABCA12 p.Asn528fs Pathogenic/Likely pathogenic ★★ same condition
ABCA12 p.Val2442fs Pathogenic ★★ same condition
ABCA12 c.5469_5472del Pathogenic ★ same condition
ABCA12 p.Arg1461fs Likely pathogenic ★ same condition
ABCA12 p.Arg248fs Likely pathogenic ★ same condition
ABCA12 p.Glu1932fs Likely pathogenic ★ same condition
ABCA12 p.Glu886fs Likely pathogenic ★ same condition
ABCA12 p.Leu217_Leu218insTer Likely 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/abca12-p-phe2286fs (accessed [today's date]).

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