Is ABCA12 p.Arg1297Ter (c.3889C>T) pathogenic?

ABCA12 p.Arg1297Ter (c.3889C>T) is classified Pathogenic in ABCA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-26). Very rare (popmax 0.00223%, eas); Associated with autosomal recessive congenital ichthyosis 4B.

What condition is associated with ABCA12 p.Arg1297Ter (c.3889C>T)?

ABCA12 p.Arg1297Ter (c.3889C>T) is associated with autosomal recessive congenital ichthyosis 4B (ClinVar).

How common is ABCA12 p.Arg1297Ter (c.3889C>T) in the general population?

ABCA12 p.Arg1297Ter (c.3889C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Harlequin ichthyosis inherited?

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

ABCA12 p.Arg1297Ter

c.3889C>T · rs114863111 · VCV265005

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

autosomal recessive congenital ichthyosis 4B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 27 of 53
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.15, phastCons 0.55
Overall
CADD	37.0	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 0.00223% East Asian · 1/44,850 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000867% 14/1,613,918 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asiangrpmax	0.00223%	44,850
European (non-Finnish)	0.000932%	107,268

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1297Ter
Coding: c.3889C>T
MANE Select: NM_173076
dbSNP: rs114863111
Type: single nucleotide variant
Location: chr2:214987734 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32
Residue 1297: a UniProt-annotated variant site (in arci4b)

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

Disease context

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

For Harlequin ichthyosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

ABCA12 c.985+1G>A Likely pathogenic ★★ same condition
ABCA12 p.Arg1515Ter Pathogenic ★★ same condition
ABCA12 p.Arg1950Ter Pathogenic ★★ same condition
ABCA12 p.Arg1960Ter Likely pathogenic ★★ same condition
ABCA12 p.Arg2204Ter Pathogenic ★★ same condition
ABCA12 p.Arg2426Gln Likely pathogenic ★★ ⚠ same condition
ABCA12 p.Arg2482Ter Pathogenic ★★ same condition
ABCA12 p.Arg287Ter 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-arg1297ter (accessed [today's date]).

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