Is ABCG8 p.His249Asp (c.745C>G) pathogenic?

ABCG8 p.His249Asp (c.745C>G) is classified Uncertain significance in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-20). AlphaMissense: ambiguous (0.4647); Absent from gnomAD v4.1.

How common is ABCG8 p.His249Asp (c.745C>G) in the general population?

ABCG8 p.His249Asp (c.745C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCG8 p.His249Asp (c.745C>G)?

AlphaMissense predicts ambiguous (score 0.4647) — an in-silico prediction, not a clinical call.

ABCG8 p.His249Asp

c.745C>G · rs1553378371 · VCV501607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4647 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4647	ambiguous
REVEL	0.398	indeterminate
SaProt	LLR -9.38	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.4, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	26.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCG8
Protein: p.His249Asp
Coding: c.745C>G
MANE Select: NM_022437
dbSNP: rs1553378371
Type: single nucleotide variant
Location: chr2:43852649 (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 249: the abc transporter domain; an α-helix

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

Similar variants

ABCG8 p.His249Pro Uncertain significance ★ ⚠ same residue
ABCG8 p.His249Tyr Uncertain significance ★ ⚠ same residue
ABCG8 c.64-2A>G Pathogenic ★★ same type
ABCG8 c.964+1G>T Likely pathogenic ★★ same type
ABCG8 c.965-1G>C Pathogenic ★★ same type
ABCG8 p.Arg121Ter Pathogenic ★★ same type
ABCG8 p.Arg164Ter Pathogenic ★★ same type
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same type

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-his249asp (accessed [today's date]).

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