Is SI p.Ala404= (c.1212G>A) pathogenic?

SI p.Ala404= (c.1212G>A) is classified Conflicting classifications of pathogenicity in SI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-27). Low-frequency (popmax 1.26%, afr); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Ala404= (c.1212G>A)?

SI p.Ala404= (c.1212G>A) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Ala404= (c.1212G>A) in the general population?

SI p.Ala404= (c.1212G>A) is low-frequency (popmax 1.26%, afr) (gnomAD).

How is Congenital sucrase-isomaltase deficiency inherited?

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

SI p.Ala404=

c.1212G>A · rs142838612 · VCV344058

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, afr)

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -3.9
Overall
CADD	3.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.26% African / African-American · 946/74,956 alleles

Filtering AF 1.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.17%

Overall 0.0697% 1,124/1,612,656 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.26%	79
Admixed American	0.0853%	1,172
Remaining individualsnot grpmax-eligible	0.0801%	1,249
Middle Eastern	0.033%	3,028
European (non-Finnish)	0.00594%	16,846
East Asian	0.00447%	22,370
Finnishnot grpmax-eligible	0.00313%	31,981
South Asian	0.0011%	91,062

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.Ala404=
Coding: c.1212G>A
MANE Select: NM_001041
dbSNP: rs142838612
Type: single nucleotide variant
Location: chr3:165059234 (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 404: the 'isomaltase' region; a turn

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.Ala404Val Uncertain significance ★★ ⚠ same residue
SI p.Ala404Gly Uncertain significance ★★ ⚠ 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
SI c.4575+2T>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-ala404 (accessed [today's date]).

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