Is ABCB4 p.Phe165Ser (c.494T>C) pathogenic?

ABCB4 p.Phe165Ser (c.494T>C) is classified Uncertain significance in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely pathogenic (0.7903); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ABCB4 p.Phe165Ser (c.494T>C)?

ABCB4 p.Phe165Ser (c.494T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ABCB4 p.Phe165Ser (c.494T>C) in the general population?

ABCB4 p.Phe165Ser (c.494T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ABCB4 p.Phe165Ser (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.7903) — an in-silico prediction, not a clinical call.

ABCB4 p.Phe165Ser

c.494T>C · VCV3291113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7903	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -13.62	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 4.6	GERP 0.66, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 1/1,461,836 · genomes 0/152,272 · 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.Phe165Ser
Coding: c.494T>C
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87452986 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 165: an α-helix; the abc transmembrane type-1 1 domain; a UniProt-annotated variant site (in gbd1)

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.Phe165Ile Uncertain significance ★ ⚠ same residue
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

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-phe165ser (accessed [today's date]).

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