Is SI c.2159+5G>C pathogenic?

SI c.2159+5G>C is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). Very rare (popmax 8.55e-05%, nfe); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI c.2159+5G>C?

SI c.2159+5G>C is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI c.2159+5G>C in the general population?

SI c.2159+5G>C is very rare (popmax 8.55e-05%, nfe) (gnomAD).

How is Congenital sucrase-isomaltase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SI c.2159+5G>C

VCV3588841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +5	donor splice region (+5, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.99	donor loss, 5 bp away · masked 0 · deltas
Pangolin	Δ0.83	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Non-coding constraint	Z -2.77	1 kb window · o/e 1.22 · regional · uncalibrated
Overall
CADD	17.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.55e-05% European (non-Finnish) · 1/1,169,128 alleles

Overall 6.24e-05% 1/1,601,580 alleles · very rare exomes 1/1,449,402 · genomes 0/152,178 · joint denominator

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
Coding: c.2159+5G>C
MANE Select: NM_001041
Type: single nucleotide variant
Location: chr3:165040935 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB

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

Disease context

congenital sucrase-isomaltase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital sucrase-isomaltase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SI c.2426+1G>A Likely pathogenic ★★ same condition
SI c.2893-1G>A Likely pathogenic ★★ same condition
SI c.3099+1G>C Likely pathogenic ★★ same condition
SI c.3521-1G>T Likely pathogenic ★★ same condition
SI c.373+1G>A Likely pathogenic ★★ same condition
SI c.4575+2T>C Likely pathogenic ★★ same condition
SI c.4927-1G>A Likely pathogenic ★★ same condition
SI c.5248-2A>C Likely pathogenic ★★ 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/si-c-2159-plus-5g-c (accessed [today's date]).

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