Is ABCB4 p.Arg549Cys (c.1645C>T) pathogenic?

ABCB4 p.Arg549Cys (c.1645C>T) is classified Likely pathogenic in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-14). AlphaMissense: likely benign (0.2333); Very rare (popmax 0.00133%, afr); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Arg549Cys (c.1645C>T)?

ABCB4 p.Arg549Cys (c.1645C>T) is associated with familial intrahepatic cholestasis (ClinVar).

How common is ABCB4 p.Arg549Cys (c.1645C>T) in the general population?

ABCB4 p.Arg549Cys (c.1645C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ABCB4 p.Arg549Cys (c.1645C>T)?

AlphaMissense predicts likely benign (score 0.2333) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg549Cys

c.1645C>T · VCV4846607

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.2333	likely benign ⚠ discordant with ClinVar
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -10.85	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	32.0	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 0.00133% African / African-American · 1/75,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,028
European (non-Finnish)	0.000169%	590,012

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.Arg549Cys
Coding: c.1645C>T
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87439753 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 549: 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

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

Similar variants

ABCB4 p.Arg549His Uncertain significance ★★ ⚠ same residue
ABCB4 p.Arg549Leu Uncertain significance ★ same residue
ABCB4 c.2064+3A>T Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2783+1G>T Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3081+1G>C Pathogenic ★★ same condition
ABCB4 c.3486+1G>A 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-arg549cys (accessed [today's date]).

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