Is ABCB4 p.Arg545His (c.1634G>A) pathogenic?

ABCB4 p.Arg545His (c.1634G>A) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.8497); Very rare (popmax 0.000254%, nfe); Associated with progressive familial intrahepatic cholestasis type 3.

What condition is associated with ABCB4 p.Arg545His (c.1634G>A)?

ABCB4 p.Arg545His (c.1634G>A) is associated with progressive familial intrahepatic cholestasis type 3, gallbladder disease 1, familial intrahepatic cholestasis (ClinVar).

How common is ABCB4 p.Arg545His (c.1634G>A) in the general population?

ABCB4 p.Arg545His (c.1634G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

What do computational predictors say about ABCB4 p.Arg545His (c.1634G>A)?

AlphaMissense predicts likely pathogenic (score 0.8497) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg545His

c.1634G>A · rs2546828022 · VCV2687819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial intrahepatic cholestasis type 3

Computational evidence

Protein change
AlphaMissense	0.8497	likely pathogenic
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -16.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	26.6	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 0.000254% European (non-Finnish) · 3/1,180,016 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,880 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: ABCB4
Protein: p.Arg545His
Coding: c.1634G>A
MANE Select: NM_000443
dbSNP: rs2546828022
Type: single nucleotide variant
Location: chr7:87439764 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 545: an α-helix; the abc transporter 1 domain; a UniProt-annotated variant site (in gbd1)

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

Disease context

progressive familial intrahepatic cholestasis type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gallbladder disease 1 familial intrahepatic cholestasis

For Progressive familial intrahepatic cholestasis (Orphanet):

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

Similar variants

ABCB4 p.Arg545Cys Pathogenic/Likely pathogenic ★★ same residue
ABCB4 p.Arg545Gly Uncertain significance ★★ ⚠ same residue
ABCB4 c.1356+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.1560+1G>A Likely pathogenic ★★ same condition
ABCB4 c.2064+3A>T 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.2783+1G>T 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-arg545his (accessed [today's date]).

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