Is ABCB4 p.Arg1109Lys (c.3326G>A) pathogenic?

ABCB4 p.Arg1109Lys (c.3326G>A) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.8439); Very rare (popmax 0.005%, amr); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Arg1109Lys (c.3326G>A)?

ABCB4 p.Arg1109Lys (c.3326G>A) is associated with familial intrahepatic cholestasis, gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Arg1109Lys (c.3326G>A) in the general population?

ABCB4 p.Arg1109Lys (c.3326G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ABCB4 p.Arg1109Lys (c.3326G>A)?

AlphaMissense predicts likely pathogenic (score 0.8439) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg1109Lys

c.3326G>A · rs757931203 · VCV502057

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.8439	likely pathogenic
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -12.15	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 14 kb · p 8.2e-06 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1116K vs ClinVar R1109K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,972 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,613,818 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,991
European (non-Finnish)	8.47e-05%	1,180,008

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.Arg1109Lys
Coding: c.3326G>A
MANE Select: NM_000443
dbSNP: rs757931203
Type: single nucleotide variant
Location: chr7:87406448 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1109: a turn; the abc transporter 2 domain

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

Also linked: gallbladder disease 1

Similar variants

ABCB4 c.1356+2T>C Pathogenic/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
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-arg1109lys (accessed [today's date]).

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