Is ABCG8 p.Ser241Phe (c.722C>T) pathogenic?

ABCG8 p.Ser241Phe (c.722C>T) is classified Conflicting classifications of pathogenicity in ABCG8 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.3405); Ultra-rare (popmax 0.0856%, sas); Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Ser241Phe (c.722C>T)?

ABCG8 p.Ser241Phe (c.722C>T) is associated with sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Ser241Phe (c.722C>T) in the general population?

ABCG8 p.Ser241Phe (c.722C>T) is ultra-rare (popmax 0.0856%, sas) (gnomAD).

How is Sitosterolemia inherited?

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

What do computational predictors say about ABCG8 p.Ser241Phe (c.722C>T)?

AlphaMissense predicts ambiguous (score 0.3405) — an in-silico prediction, not a clinical call.

ABCG8 p.Ser241Phe

c.722C>T · rs547583131 · VCV872257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.3405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0856%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

sitosterolemia 1

Computational evidence

Protein change
AlphaMissense	0.3405	ambiguous
REVEL	0.683	pathogenic-leaning
SaProt	LLR -13.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	31.0	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 0.0856% South Asian · 78/91,090 alleles

Filtering AF 0.0703% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0646%

Overall 0.018% 290/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0856%	1,168
Remaining individualsnot grpmax-eligible	0.0416%	2,404
European (non-Finnish)	0.0154%	6,484
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00267%	37,517
Finnishnot grpmax-eligible	0.00156%	64,040

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.Ser241Phe
Coding: c.722C>T
MANE Select: NM_022437
dbSNP: rs547583131
Type: single nucleotide variant
Location: chr2:43852626 (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 241: the abc transporter domain; a turn

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

ABCG8 c.64-2A>G Pathogenic ★★ same condition
ABCG8 c.965-1G>C Pathogenic ★★ same condition
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-ser241phe (accessed [today's date]).

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