Is ABCB4 p.Arg176Trp (c.526C>T) pathogenic?

ABCB4 p.Arg176Trp (c.526C>T) is classified Pathogenic/Likely pathogenic in ABCB4 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.5114); Rare (popmax 0.131%, mid); Associated with ABCB4-related disorder.

What condition is associated with ABCB4 p.Arg176Trp (c.526C>T)?

ABCB4 p.Arg176Trp (c.526C>T) is associated with ABCB4-related disorder, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Arg176Trp (c.526C>T) in the general population?

ABCB4 p.Arg176Trp (c.526C>T) is rare (popmax 0.131%, mid) (gnomAD).

What do computational predictors say about ABCB4 p.Arg176Trp (c.526C>T)?

AlphaMissense predicts ambiguous (score 0.5114) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg176Trp

c.526C>T · rs754287486 · VCV372802

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

ambiguous

0.5114 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ABCB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.5114	ambiguous
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -14.70	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.98, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	25.9	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 0.131% Middle Eastern · 8/6,084 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.00149% 24/1,613,628 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.131%	761
Remaining individualsnot grpmax-eligible	0.0016%	62,478
Finnishnot grpmax-eligible	0.00156%	63,998
African / African-American	0.00134%	74,848
South Asian	0.0011%	91,078
European (non-Finnish)	0.00102%	98,315

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.Arg176Trp
Coding: c.526C>T
MANE Select: NM_000443
dbSNP: rs754287486
Type: single nucleotide variant
Location: chr7:87452954 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 176: an α-helix; the abc transmembrane type-1 1 domain

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

Disease context

ABCB4-related disorder

Also linked: gallbladder disease 1 progressive familial intrahepatic cholestasis type 3 cholestasis, intrahepatic, of pregnancy, 3 progressive familial intrahepatic cholestasis familial intrahepatic cholestasis

Similar variants

ABCB4 p.Arg176Gln 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
ABCB4 c.286+1G>A 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-arg176trp (accessed [today's date]).

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