Is ABCB4 p.Ala511Thr (c.1531G>A) pathogenic?

ABCB4 p.Ala511Thr (c.1531G>A) is classified Likely pathogenic in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.3965); Very rare (popmax 0.00133%, afr); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Ala511Thr (c.1531G>A)?

ABCB4 p.Ala511Thr (c.1531G>A) is associated with familial intrahepatic cholestasis, gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Ala511Thr (c.1531G>A) in the general population?

ABCB4 p.Ala511Thr (c.1531G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ABCB4 p.Ala511Thr (c.1531G>A)?

AlphaMissense predicts ambiguous (score 0.3965) — an in-silico prediction, not a clinical call.

ABCB4 p.Ala511Thr

c.1531G>A · VCV4846398

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.3965	ambiguous
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -14.27	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	27.2	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 · 1/74,920 alleles

Overall 0.000124% 2/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,920
European (non-Finnish)	8.47e-05%	1,179,999

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.Ala511Thr
Coding: c.1531G>A
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87440228 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 511: the abc transporter 1 domain; a UniProt-annotated variant site (in pfic3 and 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

Also linked: gallbladder disease 1

Similar variants

ABCB4 p.Ala511= Likely benign ★ same residue
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

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-ala511thr (accessed [today's date]).

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