Is SI p.Pro1140Ala (c.3418C>G) pathogenic?

SI p.Pro1140Ala (c.3418C>G) is classified Conflicting classifications of pathogenicity in SI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-17). AlphaMissense: ambiguous (0.4929); Rare (popmax 0.136%, eas); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Pro1140Ala (c.3418C>G)?

SI p.Pro1140Ala (c.3418C>G) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Pro1140Ala (c.3418C>G) in the general population?

SI p.Pro1140Ala (c.3418C>G) is rare (popmax 0.136%, eas) (gnomAD).

How is Congenital sucrase-isomaltase deficiency inherited?

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

What do computational predictors say about SI p.Pro1140Ala (c.3418C>G)?

AlphaMissense predicts ambiguous (score 0.4929) — an in-silico prediction, not a clinical call.

SI p.Pro1140Ala

c.3418C>G · rs202077921 · VCV899494

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4929 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, eas)

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.4929	ambiguous
REVEL	0.595	indeterminate
SaProt	LLR -7.84	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.136% East Asian · 61/44,778 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0989%

Overall 0.00589% 95/1,612,162 alleles · rare exomes 83/1,460,292 · genomes 12/151,870 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.136%	734
South Asian	0.0297%	3,372
Remaining individualsnot grpmax-eligible	0.00962%	10,399
European (non-Finnish)	8.48e-05%	1,178,784

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.Pro1140Ala
Coding: c.3418C>G
MANE Select: NM_001041
dbSNP: rs202077921
Type: single nucleotide variant
Location: chr3:165019607 (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 1140: 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-pro1140ala (accessed [today's date]).

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