Is SI p.Leu296fs (c.887dup) pathogenic?

SI p.Leu296fs (c.887dup) is classified Pathogenic in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). Very rare (popmax 0.00155%, nfe).

How common is SI p.Leu296fs (c.887dup) in the general population?

SI p.Leu296fs (c.887dup) is very rare (popmax 0.00155%, nfe) (gnomAD).

SI p.Leu296fs

c.887dup · rs769103567 · VCV1452198

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00155%, 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 8 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.096	GERP -3.9, phastCons 0.98
Overall
CADD	33.0	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 0.00155% European (non-Finnish) · 17/1,097,544 alleles

Filtering AF 0.000943% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000771%

Overall 0.00256% 39/1,520,762 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0283%	3,534
Remaining individualsnot grpmax-eligible	0.00507%	19,741
European (non-Finnish)grpmax	0.00155%	64,562
African / African-American	0.00137%	73,010

Finnish 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: SI
Protein: p.Leu296fs
Coding: c.887dup
MANE Select: NM_001041
dbSNP: rs769103567
Type: Duplication
Location: chr3:165063461 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 296: the 'isomaltase' region; a β-strand

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

Similar variants

SI p.Gln677fs Pathogenic/Likely pathogenic ★★ same type
SI p.His1210fs Pathogenic/Likely pathogenic ★★ same type
SI p.Phe1366fs Pathogenic/Likely pathogenic ★★ same type
SI c.119-11dup Benign/Likely benign ★★ same type
SI c.2737-23dup Benign/Likely benign ★★ same type
SI c.374-11dup Benign/Likely benign ★★ same type
SI c.5198-20dup Benign/Likely benign ★★ same type
SI p.Asn1027fs 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/si-p-leu296fs (accessed [today's date]).

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