Is ABCB11 p.Thr227= (c.681C>A) pathogenic?

ABCB11 p.Thr227= (c.681C>A) is classified Conflicting classifications of pathogenicity in ABCB11 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-05). Very rare (popmax 0.000848%, nfe); Associated with progressive familial intrahepatic cholestasis type 2.

What condition is associated with ABCB11 p.Thr227= (c.681C>A)?

ABCB11 p.Thr227= (c.681C>A) is associated with progressive familial intrahepatic cholestasis type 2 (ClinVar).

How common is ABCB11 p.Thr227= (c.681C>A) in the general population?

ABCB11 p.Thr227= (c.681C>A) is very rare (popmax 0.000848%, nfe) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

ABCB11 p.Thr227=

c.681C>A · rs1401834885 · VCV894543

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Conditions

progressive familial intrahepatic cholestasis type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	GERP -0.8, phastCons 0.99
Overall
CADD	9.075	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,178,648 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000621% 10/1,611,482 alleles · very 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: ABCB11
Protein: p.Thr227=
Coding: c.681C>A
MANE Select: NM_003742
dbSNP: rs1401834885
Type: single nucleotide variant
Location: chr2:168993813 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.23 · 9 PDB
Residue 227: an α-helix; the abc transmembrane type-1 1 domain

Full ABCB11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive familial intrahepatic cholestasis type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive familial intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

ABCB11 c.1084-2A>G Pathogenic ★★ same condition
ABCB11 c.1198-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1198-2A>C Likely pathogenic ★★ same condition
ABCB11 c.150+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.150+3A>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1638+1G>C Likely pathogenic ★★ same condition
ABCB11 c.1810-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.2011+1G>T 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/abcb11-p-thr227 (accessed [today's date]).

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