Is ABCC2 p.Ser1168fs (c.3500dup) pathogenic?

ABCC2 p.Ser1168fs (c.3500dup) is classified Pathogenic in ABCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-04). Very rare (popmax 0.00167%, amr).

How common is ABCC2 p.Ser1168fs (c.3500dup) in the general population?

ABCC2 p.Ser1168fs (c.3500dup) is very rare (popmax 0.00167%, amr) (gnomAD).

ABCC2 p.Ser1168fs

c.3500dup · rs1333544687 · VCV498805

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 25 of 32
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.6	GERP 1.7, phastCons 1
Overall
CADD	35.0	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000805% 13/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,239
Admixed Americangrpmax	0.00167%	60,002
African / African-American	0.00133%	74,928
European (non-Finnish)	0.000763%	131,116

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser1168fs
Coding: c.3500dup
MANE Select: NM_000392
dbSNP: rs1333544687
Type: Duplication
Location: chr10:99836175 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 1168: an α-helix; the abc transmembrane type-1 2 domain

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

Similar variants

ABCC2 p.Asp1073Ter Pathogenic ★★ same type
ABCC2 p.Leu1213fs Pathogenic ★★ same type
ABCC2 p.Lys298fs Pathogenic ★★ same type
ABCC2 p.Val667fs Pathogenic/Likely pathogenic ★★ same type
ABCC2 p.Ala579fs Pathogenic ★ same type
ABCC2 p.Asp210Ter Pathogenic ★ same type
ABCC2 p.Asp304fs Likely pathogenic ★ same type
ABCC2 p.Gly853fs 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-ser1168fs (accessed [today's date]).

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