Is ABCC2 p.Phe539fs (c.1617del) pathogenic?

ABCC2 p.Phe539fs (c.1617del) is classified Pathogenic in ABCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-25). Very rare (popmax 0.000339%, nfe).

How common is ABCC2 p.Phe539fs (c.1617del) in the general population?

ABCC2 p.Phe539fs (c.1617del) is very rare (popmax 0.000339%, nfe) (gnomAD).

ABCC2 p.Phe539fs

c.1617del · VCV3681295

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 32
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.8	GERP -4.9
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,004 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,022 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: ABCC2
Protein: p.Phe539fs
Coding: c.1617del
MANE Select: NM_000392
Type: Deletion
Location: chr10:99807468 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 539: an α-helix; the abc transmembrane type-1 1 domain

Full ABCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC2 p.Asn159fs Pathogenic ★★ same type
ABCC2 p.Asn718fs Pathogenic/Likely pathogenic ★★ same type
ABCC2 p.Ile754fs Pathogenic ★★ same type
ABCC2 p.Leu431fs Pathogenic ★★ same type
ABCC2 p.Leu788fs Pathogenic/Likely pathogenic ★★ same type
ABCC2 p.Leu809fs Pathogenic/Likely pathogenic ★★ same type
ABCC2 p.Pro194_Ser195insTer Pathogenic ★★ same type
ABCC2 p.Pro274fs 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/abcc2-p-phe539fs (accessed [today's date]).

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