Is ABCG8 p.Phe595= (c.1785C>T) pathogenic?

ABCG8 p.Phe595= (c.1785C>T) is classified Conflicting classifications of pathogenicity in ABCG8 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-02). Rare (popmax 0.224%, nfe); Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Phe595= (c.1785C>T)?

ABCG8 p.Phe595= (c.1785C>T) is associated with sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Phe595= (c.1785C>T) in the general population?

ABCG8 p.Phe595= (c.1785C>T) is rare (popmax 0.224%, nfe) (gnomAD).

How is Sitosterolemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCG8 p.Phe595=

c.1785C>T · rs139677898 · VCV336091

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.224%, nfe)

Conditions

sitosterolemia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.42, phastCons 1
Overall
CADD	14.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.224% European (non-Finnish) · 2,646/1,180,022 alleles

Filtering AF 0.217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.214%

Overall 0.176% 2,837/1,614,098 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.224%	446
Remaining individualsnot grpmax-eligible	0.195%	512
Middle Eastern	0.0496%	2,016
African / African-American	0.0427%	2,344
Admixed American	0.04%	2,501
Finnishnot grpmax-eligible	0.00937%	10,671
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.00329%	30,361

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: ABCG8
Protein: p.Phe595=
Coding: c.1785C>T
MANE Select: NM_022437
dbSNP: rs139677898
Type: single nucleotide variant
Location: chr2:43877589 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 8 PDB
Residue 595: the abc transmembrane type-2 domain; an α-helix

Full ABCG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

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ABCG8 p.Arg164Ter Pathogenic ★★ same condition
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG8 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Gly574Arg Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Ser107Ter Pathogenic ★★ same condition
ABCG8 p.Trp361Ter 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/abcg8-p-phe595 (accessed [today's date]).

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