Is ABCB11 p.Val444Ala (c.1331T>C) pathogenic?

ABCB11 p.Val444Ala (c.1331T>C) is classified Benign in ABCB11 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.1104); Common (popmax 72.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB11 p.Val444Ala (c.1331T>C)?

ABCB11 p.Val444Ala (c.1331T>C) is associated with familial intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2, benign recurrent intrahepatic cholestasis type 2 (ClinVar).

What do computational predictors say about ABCB11 p.Val444Ala (c.1331T>C)?

AlphaMissense predicts likely benign (score 0.1104) — an in-silico prediction, not a clinical call.

ABCB11 p.Val444Ala

Q: How common is ABCB11 p.Val444Ala (c.1331T>C) in the general population?

ABCB11 p.Val444Ala (c.1331T>C) is common (popmax 72.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1331T>C · rs2287622 · VCV194214

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1104 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 72.7%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.1104	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.89, phastCons 0.96
Overall
CADD	18.15	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 72.7% East Asian · 32,529/44,772 alleles

Filtering AF 72% ClinGen BA1/BS1 input FAF95, joint · FAF99 71.7%

Overall 59.1% 951,520/1,610,750 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	72.7%	1
Amishnot grpmax-eligible	66%	2
European (non-Finnish)	60.2%	2
Remaining individualsnot grpmax-eligible	58.7%	2
Middle Eastern	58.3%	2
African / African-American	57.2%	2
South Asian	56.9%	2
Ashkenazi Jewishnot grpmax-eligible	56.5%	2
Finnishnot grpmax-eligible	51.2%	2
Admixed American	43.4%	2

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: ABCB11
Protein: p.Val444Ala
Coding: c.1331T>C
MANE Select: NM_003742
dbSNP: rs2287622
Type: single nucleotide variant
Location: chr2:168973818 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.23 · 9 PDB
Residue 444: the abc transporter 1 domain; a UniProt-annotated variant site (does not affect transport capacity for taurocholate; increases transport activity of taurocholate in a low cholesterol environment; increases transport activity of taurocholate in a high cholesterol environment; does not affect cell surface protein expression; does not affect protein expression); a UniProt-annotated variant site (in)

Full ABCB11 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 2 benign recurrent intrahepatic cholestasis type 2

Similar variants

ABCB11 p.Val444Asp Uncertain significance ★ ⚠ same residue
ABCB11 p.Val444Gly Uncertain significance ★ ⚠ same residue
ABCB11 c.1084-2A>G Pathogenic ★★ same condition
ABCB11 c.1197+1G>T Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1198-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1198-2A>C Likely pathogenic ★★ same condition
ABCB11 c.1435-2A>T Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.150+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/abcb11-p-val444ala (accessed [today's date]).

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