Is ABCG5 p.Arg408Ter (c.1222C>T) pathogenic?

ABCG5 p.Arg408Ter (c.1222C>T) is classified Pathogenic/Likely pathogenic in ABCG5 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-22). Very rare (popmax 0.0022%, sas); Associated with sitosterolemia 2.

What condition is associated with ABCG5 p.Arg408Ter (c.1222C>T)?

ABCG5 p.Arg408Ter (c.1222C>T) is associated with sitosterolemia 2, sitosterolemia (ClinVar).

How common is ABCG5 p.Arg408Ter (c.1222C>T) in the general population?

ABCG5 p.Arg408Ter (c.1222C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Sitosterolemia inherited?

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

ABCG5 p.Arg408Ter

c.1222C>T · rs119479065 · VCV4976

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

sitosterolemia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 13
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 0.95, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,094 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000743% 12/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,547
Admixed American	0.00167%	59,988
European (non-Finnish)	0.000763%	131,116

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: ABCG5
Protein: p.Arg408Ter
Coding: c.1222C>T
MANE Select: NM_022436
dbSNP: rs119479065
Type: single nucleotide variant
Location: chr2:43824015 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 8 PDB
Residue 408: the abc transmembrane type-2 domain

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sitosterolemia

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 p.Arg408Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.634+1G>C Likely pathogenic ★★ same condition
ABCG5 c.904+1G>A Pathogenic ★★ same condition
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His 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/abcg5-p-arg408ter (accessed [today's date]).

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