Is ABCB4 p.Ala578Val (c.1733C>T) pathogenic?

ABCB4 p.Ala578Val (c.1733C>T) is classified Pathogenic in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-01). AlphaMissense: likely benign (0.114); Very rare (popmax 0.00153%, nfe); Associated with progressive familial intrahepatic cholestasis type 3.

What condition is associated with ABCB4 p.Ala578Val (c.1733C>T)?

ABCB4 p.Ala578Val (c.1733C>T) is associated with progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Ala578Val (c.1733C>T) in the general population?

ABCB4 p.Ala578Val (c.1733C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

What do computational predictors say about ABCB4 p.Ala578Val (c.1733C>T)?

AlphaMissense predicts likely benign (score 0.114) — an in-silico prediction, not a clinical call.

ABCB4 p.Ala578Val

c.1733C>T · rs756419705 · VCV2687811

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.114 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial intrahepatic cholestasis type 3

Computational evidence

Protein change
AlphaMissense	0.114	likely benign ⚠ discordant with ClinVar
REVEL	0.288	benign-leaning
SaProt	LLR -12.30	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	23.5	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 0.00153% European (non-Finnish) · 18/1,179,910 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,613,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)grpmax	0.00153%	65,551

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala578Val
Coding: c.1733C>T
MANE Select: NM_000443
dbSNP: rs756419705
Type: single nucleotide variant
Location: chr7:87431564 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 578: an α-helix; the abc transporter 1 domain

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

Disease context

progressive familial intrahepatic cholestasis type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive familial intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

ABCB4 p.Ala578Ser Uncertain significance ★ ⚠ same residue
CROT p.Cys578Ser Uncertain significance ★ ⚠ same residue
ABCB4 p.Ala578= Likely benign ★ same residue
ABCB4 c.1560+1G>A 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.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-ala578val (accessed [today's date]).

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