Is ABCB4 p.Val1270Phe (c.3808G>T) pathogenic?

ABCB4 p.Val1270Phe (c.3808G>T) is classified Uncertain significance in ABCB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.186); Very rare (popmax 0.000254%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Val1270Phe (c.3808G>T)?

ABCB4 p.Val1270Phe (c.3808G>T) is associated with familial intrahepatic cholestasis, gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Val1270Phe (c.3808G>T) in the general population?

ABCB4 p.Val1270Phe (c.3808G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ABCB4 p.Val1270Phe (c.3808G>T)?

AlphaMissense predicts likely benign (score 0.186) — an in-silico prediction, not a clinical call.

ABCB4 p.Val1270Phe

c.3808G>T · VCV4077765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.186	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.50	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.21	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 183 bp · p 0.039 · regional, not allelic
Overall
CADD	29.0	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 V1277F vs ClinVar V1270F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,042 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,928 alleles · very rare exomes 1/1,461,754 · genomes 2/152,174 · 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.Val1270Phe
Coding: c.3808G>T
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87402128 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1277 UniProt numbering: the abc transporter 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

Also linked: gallbladder disease 1

Similar variants

ABCB4 c.1356+2T>C Pathogenic/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
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-val1270phe (accessed [today's date]).

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