Is SI p.Lys1033= (c.3099G>A) pathogenic?

SI p.Lys1033= (c.3099G>A) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-29). Very rare (popmax 0.00655%, nfe); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Lys1033= (c.3099G>A)?

SI p.Lys1033= (c.3099G>A) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Lys1033= (c.3099G>A) in the general population?

SI p.Lys1033= (c.3099G>A) is very rare (popmax 0.00655%, nfe) (gnomAD).

How is Congenital sucrase-isomaltase deficiency inherited?

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

SI p.Lys1033=

c.3099G>A · rs201844171 · VCV2976983

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00655%, 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
SpliceAI	Δ0.95	donor loss · deltas
Pangolin	Δ0.77	loss · gain 0.52 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00655% European (non-Finnish) · 77/1,175,202 alleles

Filtering AF 0.00532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00492%

Overall 0.00516% 83/1,607,500 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00655%	15,262
Remaining individualsnot grpmax-eligible	0.00483%	20,723
East Asian	0.00224%	44,674
Finnishnot grpmax-eligible	0.00156%	63,920
African / African-American	0.00134%	74,550

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.Lys1033=
Coding: c.3099G>A
MANE Select: NM_001041
dbSNP: rs201844171
Type: single nucleotide variant
Location: chr3:165023570 (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 1033: the 'sucrase' region

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-p-lys1033 (accessed [today's date]).

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