Is ABCB4 p.Arg406Gln (c.1217G>A) pathogenic?

ABCB4 p.Arg406Gln (c.1217G>A) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.4387); Very rare (popmax 0.00659%, sas); Associated with gallbladder disease 1.

What condition is associated with ABCB4 p.Arg406Gln (c.1217G>A)?

ABCB4 p.Arg406Gln (c.1217G>A) is associated with gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Arg406Gln (c.1217G>A) in the general population?

ABCB4 p.Arg406Gln (c.1217G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

How is Low phospholipid-associated cholelithiasis inherited?

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

What do computational predictors say about ABCB4 p.Arg406Gln (c.1217G>A)?

AlphaMissense predicts ambiguous (score 0.4387) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg406Gln

c.1217G>A · rs763807769 · VCV1396149

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

gallbladder disease 1

Computational evidence

Protein change
AlphaMissense	0.4387	ambiguous
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -11.73	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	27.5	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 0.00659% South Asian · 6/91,058 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00124% 20/1,613,368 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,176
African / African-American	0.00267%	37,450
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000933%	107,229

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.Arg406Gln
Coding: c.1217G>A
MANE Select: NM_000443
dbSNP: rs763807769
Type: single nucleotide variant
Location: chr7:87443676 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 406: a β-strand; the abc transporter 1 domain; a binding site; a UniProt-annotated variant site (in gbd1); a UniProt-annotated variant site (found in patients with cholangitis; uncertain significance)

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

Disease context

gallbladder disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Low phospholipid-associated cholelithiasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

ABCB4 p.Arg406Ter Pathogenic/Likely pathogenic ★★ same residue
ABCB4 c.1356+2T>C Pathogenic/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.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.3486+5G>A Likely pathogenic ★★ same condition
ABCB4 c.80+1G>A 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-arg406gln (accessed [today's date]).

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