Is ABCB4 p.Pro404Ala (c.1210C>G) pathogenic?

ABCB4 p.Pro404Ala (c.1210C>G) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.4708); Ultra-rare (popmax 0.0165%, mid); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Pro404Ala (c.1210C>G)?

ABCB4 p.Pro404Ala (c.1210C>G) is associated with familial intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 1 (ClinVar).

How common is ABCB4 p.Pro404Ala (c.1210C>G) in the general population?

ABCB4 p.Pro404Ala (c.1210C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCB4 p.Pro404Ala (c.1210C>G)?

AlphaMissense predicts ambiguous (score 0.4708) — an in-silico prediction, not a clinical call.

ABCB4 p.Pro404Ala

c.1210C>G · rs863225298 · VCV242455

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.4708	ambiguous
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -10.65	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	25.5	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000124% 2/1,613,746 alleles · ultra-rare exomes 2/1,461,508 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Pro404Ala
Coding: c.1210C>G
MANE Select: NM_000443
dbSNP: rs863225298
Type: single nucleotide variant
Location: chr7:87443683 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 404: a β-strand; the abc transporter 1 domain

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: progressive familial intrahepatic cholestasis type 1

Similar variants

ABCB4 p.Pro404Ser Uncertain significance ★ ⚠ same residue
CROT p.Phe404Leu Uncertain significance ★ ⚠ same residue
ABCB4 c.2064+3A>T 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
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-pro404ala (accessed [today's date]).

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