Is ABCB4 p.Thr175Ala (c.523A>G) pathogenic?

ABCB4 p.Thr175Ala (c.523A>G) is classified Benign/Likely benign in ABCB4 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.1388); Low-frequency (popmax 1.35%, sas); Associated with progressive familial intrahepatic cholestasis type 3.

What condition is associated with ABCB4 p.Thr175Ala (c.523A>G)?

ABCB4 p.Thr175Ala (c.523A>G) is associated with progressive familial intrahepatic cholestasis type 3, gallbladder disease 1, cholestasis, intrahepatic, of pregnancy, 3 (ClinVar).

How common is ABCB4 p.Thr175Ala (c.523A>G) in the general population?

ABCB4 p.Thr175Ala (c.523A>G) is low-frequency (popmax 1.35%, sas) (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.Thr175Ala (c.523A>G)?

AlphaMissense predicts likely benign (score 0.1388) — an in-silico prediction, not a clinical call.

ABCB4 p.Thr175Ala

c.523A>G · rs58238559 · VCV13691

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1388 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.35%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive familial intrahepatic cholestasis type 3

Computational evidence

Protein change
AlphaMissense	0.1388	likely benign
REVEL	0.581	indeterminate
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	25.0	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 1.35% South Asian · 1,232/91,078 alleles

Filtering AF 1.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.26%

Overall 0.933% 15,065/1,613,900 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.64%	27
South Asiangrpmax	1.35%	74
Amishnot grpmax-eligible	0.987%	101
European (non-Finnish)	0.87%	115
Admixed American	0.77%	130
Remaining individualsnot grpmax-eligible	0.754%	133
Ashkenazi Jewishnot grpmax-eligible	0.49%	204
Middle Eastern	0.462%	216
African / African-American	0.127%	790
East Asian	0.0624%	1,603

Finnish 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.Thr175Ala
Coding: c.523A>G
MANE Select: NM_000443
dbSNP: rs58238559
Type: single nucleotide variant
Location: chr7:87452957 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 175: an α-helix; the abc transmembrane type-1 1 domain; a UniProt-annotated variant site (found in patients with gallbladder and cholestasis; uncertain significance)

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

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

For Progressive familial intrahepatic cholestasis (Orphanet):

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

Similar variants

ABCB4 p.Thr175Lys Uncertain significance ★ ⚠ same residue
ABCB4 p.Thr175Met Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCB4 p.Thr175= Conflicting classifications of pathogenicity ★ 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

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-thr175ala (accessed [today's date]).

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