Is ABCB4 p.Ile738Phe (c.2212A>T) pathogenic?

ABCB4 p.Ile738Phe (c.2212A>T) is classified Uncertain significance in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.4078); Absent from gnomAD v4.1; Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Ile738Phe (c.2212A>T)?

ABCB4 p.Ile738Phe (c.2212A>T) is associated with familial intrahepatic cholestasis (ClinVar).

How common is ABCB4 p.Ile738Phe (c.2212A>T) in the general population?

ABCB4 p.Ile738Phe (c.2212A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCB4 p.Ile738Phe (c.2212A>T)?

AlphaMissense predicts ambiguous (score 0.4078) — an in-silico prediction, not a clinical call.

ABCB4 p.Ile738Phe

c.2212A>T · VCV4846511

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4078 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.4078	ambiguous
REVEL	0.465	indeterminate
SaProt	LLR -10.92	damaging
Splicing
SpliceAI	Δ0.37	acceptor loss · deltas
Pangolin	Δ0.44	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.66	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.53 · regional, not allelic
Overall
CADD	18.23	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCB4
Protein: p.Ile738Phe
Coding: c.2212A>T
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87422225 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 738: an α-helix; the abc transmembrane type-1 2 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

Similar variants

ABCB4 p.Ile738Leu Uncertain significance ★★ ⚠ same residue
ABCB4 p.Ile738Val 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-ile738phe (accessed [today's date]).

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