Is ABCG8 p.Leu115Pro (c.344T>C) pathogenic?

ABCG8 p.Leu115Pro (c.344T>C) is classified Uncertain significance in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely pathogenic (0.6406); Very rare (popmax 0.000593%, nfe).

How common is ABCG8 p.Leu115Pro (c.344T>C) in the general population?

ABCG8 p.Leu115Pro (c.344T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about ABCG8 p.Leu115Pro (c.344T>C)?

AlphaMissense predicts likely pathogenic (score 0.6406) — an in-silico prediction, not a clinical call.

ABCG8 p.Leu115Pro

c.344T>C · VCV3360829

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6406	likely pathogenic
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,034 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,888 alleles · very rare

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.Leu115Pro
Coding: c.344T>C
MANE Select: NM_022437
Type: single nucleotide variant
Location: chr2:43851605 (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 115: 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.Leu115= Likely benign ★ 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
ABCG8 p.Arg412Ter 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-leu115pro (accessed [today's date]).

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