Is ABCB4 p.Val1138Phe (c.3412G>T) pathogenic?

ABCB4 p.Val1138Phe (c.3412G>T) is classified Uncertain significance in ABCB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-21). AlphaMissense: likely benign (0.1005); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ABCB4 p.Val1138Phe (c.3412G>T)?

ABCB4 p.Val1138Phe (c.3412G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ABCB4 p.Val1138Phe (c.3412G>T) in the general population?

ABCB4 p.Val1138Phe (c.3412G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCB4 p.Val1138Phe (c.3412G>T)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

ABCB4 p.Val1138Phe

c.3412G>T · VCV3972636

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.31	donor loss, 20 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.7	GERP -3.7
Regional constraint	o/e 0.77	unconstrained · MANE · 14 kb · p 8.2e-06 · regional, not allelic
Overall
CADD	15.75	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V1145F vs ClinVar V1138F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Overall 6.2e-05% 1/1,613,916 alleles · very rare exomes 0/1,461,878 · genomes 1/152,038 · joint denominator

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.Val1138Phe
Coding: c.3412G>T
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87406362 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1145 UniProt numbering: the abc transporter 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCB4 p.Ala1005Thr Uncertain significance ★★ ⚠ same condition
ABCB4 p.Ala304Ser Uncertain significance ★★ ⚠ same condition
ABCB4 p.Ala333Thr Uncertain significance ★★ ⚠ same condition
ABCB4 p.Arg159Gln Uncertain significance ★★ ⚠ same condition
ABCB4 p.Arg661His Uncertain significance ★★ ⚠ same condition
ABCB4 p.Arg969Cys Uncertain significance ★★ ⚠ same condition
ABCB4 p.Cys1226Gly Uncertain significance ★★ ⚠ same condition
ABCB4 p.Cys955Gly Uncertain significance ★★ 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-val1138phe (accessed [today's date]).

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