Is ABCB4 p.Ser320Phe (c.959C>T) pathogenic?

ABCB4 p.Ser320Phe (c.959C>T) is classified Pathogenic/Likely pathogenic in ABCB4 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-09-01). AlphaMissense: likely pathogenic (0.6872); Ultra-rare (popmax 0.022%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Ser320Phe (c.959C>T)?

ABCB4 p.Ser320Phe (c.959C>T) is associated with familial intrahepatic cholestasis, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Ser320Phe (c.959C>T) in the general population?

ABCB4 p.Ser320Phe (c.959C>T) is ultra-rare (popmax 0.022%, nfe) (gnomAD).

What do computational predictors say about ABCB4 p.Ser320Phe (c.959C>T)?

AlphaMissense predicts likely pathogenic (score 0.6872) — an in-silico prediction, not a clinical call.

ABCB4 p.Ser320Phe

c.959C>T · rs72552778 · VCV13690

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.6872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.6872	likely pathogenic ✓ concordant with ClinVar
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -10.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	28.4	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 0.022% European (non-Finnish) · 259/1,179,716 alleles

Filtering AF 0.0197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0189%

Overall 0.0174% 280/1,613,618 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.022%	4,555
Admixed American	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0128%	7,809
South Asian	0.00329%	30,357
African / African-American	0.00267%	37,453

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.Ser320Phe
Coding: c.959C>T
MANE Select: NM_000443
dbSNP: rs72552778
Type: single nucleotide variant
Location: chr7:87447080 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 320: an α-helix; the abc transmembrane type-1 1 domain; a UniProt-annotated variant site (in icp3, gbd1 and pfic3; uncertain significance; does not alter plasma membrane location; does not inhibit efflux activity for pc)

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 progressive familial intrahepatic cholestasis type 3 cholestasis, intrahepatic, of pregnancy, 3 progressive familial intrahepatic cholestasis

Similar variants

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
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

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-ser320phe (accessed [today's date]).

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