Is SI p.Glu285Ter (c.853G>T) pathogenic?

SI p.Glu285Ter (c.853G>T) is classified Pathogenic/Likely pathogenic in SI (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-20). Ultra-rare (popmax 0.0337%, mid); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Glu285Ter (c.853G>T)?

SI p.Glu285Ter (c.853G>T) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Glu285Ter (c.853G>T) in the general population?

SI p.Glu285Ter (c.853G>T) is ultra-rare (popmax 0.0337%, mid) (gnomAD).

How is Congenital sucrase-isomaltase deficiency inherited?

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

SI p.Glu285Ter

c.853G>T · rs758259365 · VCV489002

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, mid)

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 48
Splicing
SpliceAI	Δ0.71	acceptor loss · deltas
Pangolin	Δ0.55	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	44.0	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 0.0337% Middle Eastern · 2/5,936 alleles

Filtering AF 0.00593% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00246%

Overall 0.000566% 8/1,413,672 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0337%	2,968
Admixed American	0.00169%	59,268
Finnishnot grpmax-eligible	0.00158%	63,220
South Asian	0.00114%	87,968
European (non-Finnish)	0.000263%	380,152

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.Glu285Ter
Coding: c.853G>T
MANE Select: NM_001041
dbSNP: rs758259365
Type: single nucleotide variant
Location: chr3:165063496 (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 285: the 'isomaltase' 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-glu285ter (accessed [today's date]).

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