Is ABCG8 p.Asp237His (c.709G>C) pathogenic?

ABCG8 p.Asp237His (c.709G>C) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: ambiguous (0.4824); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Asp237His (c.709G>C)?

ABCG8 p.Asp237His (c.709G>C) is associated with Cardiovascular phenotype, sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Asp237His (c.709G>C) in the general population?

ABCG8 p.Asp237His (c.709G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ABCG8 p.Asp237His (c.709G>C)?

AlphaMissense predicts ambiguous (score 0.4824) — an in-silico prediction, not a clinical call.

ABCG8 p.Asp237His

c.709G>C · rs201868259 · VCV2557357

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4824	ambiguous
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -12.13	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	32.0	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 0.00133% African / African-American · 1/75,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,876 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,028
European (non-Finnish)	0.000169%	590,005

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.Asp237His
Coding: c.709G>C
MANE Select: NM_022437
dbSNP: rs201868259
Type: single nucleotide variant
Location: chr2:43852613 (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 237: the abc transporter domain; a β-strand

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sitosterolemia 1

Similar variants

ABCG8 p.Asp237Val Uncertain significance ★★ ⚠ same residue
ABCG8 p.Asp237= Likely benign ★★ same residue
ABCG8 p.Asp237Asn Uncertain significance ★★ ⚠ same residue
ABCG8 c.64-2A>G Pathogenic ★★ same condition
ABCG8 c.965-1G>C Pathogenic ★★ same condition
ABCG8 p.Arg121Ter Pathogenic ★★ same condition
ABCG8 p.Arg164Ter Pathogenic ★★ same condition
ABCG8 p.Arg405Cys 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-asp237his (accessed [today's date]).

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