Is ABCG5 p.Phe129Ser (c.386T>C) pathogenic?

ABCG5 p.Phe129Ser (c.386T>C) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-24). AlphaMissense: ambiguous (0.4729); Ultra-rare (popmax 0.0171%, mid); Associated with Cardiovascular phenotype.

What condition is associated with ABCG5 p.Phe129Ser (c.386T>C)?

ABCG5 p.Phe129Ser (c.386T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG5 p.Phe129Ser (c.386T>C) in the general population?

ABCG5 p.Phe129Ser (c.386T>C) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about ABCG5 p.Phe129Ser (c.386T>C)?

AlphaMissense predicts ambiguous (score 0.4729) — an in-silico prediction, not a clinical call.

ABCG5 p.Phe129Ser

c.386T>C · rs901129455 · VCV2619758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4729	ambiguous
REVEL	0.662	pathogenic-leaning
SaProt	LLR -2.46	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 0.57, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.6	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 0.0171% Middle Eastern · 1/5,834 alleles

Overall 0.000143% 2/1,398,418 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,834
East Asian	0.00244%	41,060

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.Phe129Ser
Coding: c.386T>C
MANE Select: NM_022436
dbSNP: rs901129455
Type: single nucleotide variant
Location: chr2:43831963 (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 129: the abc transporter domain; a β-strand

Full ABCG5 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

Similar variants

ABCG5 c.1325-1G>T Likely pathogenic ★★ same condition
ABCG5 p.Gln251Ter Pathogenic ★★ same condition
ABCG5 p.Glu146Ter Pathogenic ★★ same condition
ABCG5 p.Ala170Asp Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala264Val Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala278Glu Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala333Ser Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala429Thr Uncertain significance ★★ ⚠ 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-phe129ser (accessed [today's date]).

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