Is ABCG5 p.Ser618Pro (c.1852T>C) pathogenic?

ABCG5 p.Ser618Pro (c.1852T>C) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1621); Very rare (popmax 0.00333%, amr).

How common is ABCG5 p.Ser618Pro (c.1852T>C) in the general population?

ABCG5 p.Ser618Pro (c.1852T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ABCG5 p.Ser618Pro (c.1852T>C)?

AlphaMissense predicts likely benign (score 0.1621) — an in-silico prediction, not a clinical call.

ABCG5 p.Ser618Pro

c.1852T>C · VCV4540637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1621	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.74, phastCons 0.8
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00333% Admixed American · 2/59,986 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00124% 20/1,612,078 alleles · very rare exomes 18/1,459,878 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,993
Remaining individualsnot grpmax-eligible	0.0016%	62,396
European (non-Finnish)	0.00144%	69,314

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.Ser618Pro
Coding: c.1852T>C
MANE Select: NM_022436
Type: single nucleotide variant
Location: chr2:43813220 (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 618: the abc transmembrane type-2 domain; an α-helix

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCG5 p.Ser618Phe Uncertain significance ★ ⚠ same residue
ABCG5 c.1325-1G>T Likely pathogenic ★★ same type
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same type
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCG5 c.634+1G>C Likely pathogenic ★★ same type
ABCG5 c.904+1G>A Pathogenic ★★ same type
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same type
ABCG5 p.Arg243Ter 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/abcg5-p-ser618pro (accessed [today's date]).

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