Is SI p.Ala1245Asp (c.3734C>A) pathogenic?

SI p.Ala1245Asp (c.3734C>A) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-28). AlphaMissense: likely benign (0.0938); Very rare (popmax 0.00134%, afr); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Ala1245Asp (c.3734C>A)?

SI p.Ala1245Asp (c.3734C>A) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Ala1245Asp (c.3734C>A) in the general population?

SI p.Ala1245Asp (c.3734C>A) is very rare (popmax 0.00134%, afr) (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.Ala1245Asp (c.3734C>A)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

SI p.Ala1245Asp

c.3734C>A · VCV3588798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.1	GERP -3.9
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,764 alleles

Overall 0.000659% 1/151,716 alleles · very rare

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.Ala1245Asp
Coding: c.3734C>A
MANE Select: NM_001041
Type: single nucleotide variant
Location: chr3:165017573 (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 1245: 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 p.Ala1245Val Uncertain significance ★ ⚠ same residue
SI p.Ala1245Thr Uncertain significance ★ ⚠ same residue
SI p.Ala1245= Likely benign ★ same residue
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

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-ala1245asp (accessed [today's date]).

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