Is ABCB4 p.Leu1196= (c.3588C>T) pathogenic?

ABCB4 p.Leu1196= (c.3588C>T) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-23). Very rare (popmax 0.000847%, nfe); Associated with cholestasis, intrahepatic, of pregnancy, 3.

What condition is associated with ABCB4 p.Leu1196= (c.3588C>T)?

ABCB4 p.Leu1196= (c.3588C>T) is associated with cholestasis, intrahepatic, of pregnancy, 3, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Leu1196= (c.3588C>T) in the general population?

ABCB4 p.Leu1196= (c.3588C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

How is Intrahepatic cholestasis of pregnancy inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ABCB4 p.Leu1196=

c.3588C>T · rs370310867 · VCV911979

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Conditions

cholestasis, intrahepatic, of pregnancy, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.268	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7	GERP -3.7
Overall
CADD	0.433	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,179,990 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00155% 25/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)grpmax	0.000847%	117,999

Ashkenazi Jewish 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: ABCB4
Protein: p.Leu1196=
Coding: c.3588C>T
MANE Select: NM_000443
dbSNP: rs370310867
Type: single nucleotide variant
Location: chr7:87403180 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1196: an α-helix; the abc transporter 2 domain

Full ABCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cholestasis, intrahepatic, of pregnancy, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial intrahepatic cholestasis type 3

For Intrahepatic cholestasis of pregnancy (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: Adult

Similar variants

ABCB4 p.Leu1196Phe Uncertain significance ★ ⚠ same residue
ABCB4 c.1560+1G>A Likely pathogenic ★★ same condition
ABCB4 c.2211+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.3081+1G>C Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.834-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Arg1046Ter Pathogenic/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/abcb4-p-leu1196 (accessed [today's date]).

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