Is SI p.Arg250His (c.749G>A) pathogenic?

SI p.Arg250His (c.749G>A) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.1761); Ultra-rare (popmax 0.0242%, sas); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Arg250His (c.749G>A)?

SI p.Arg250His (c.749G>A) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Arg250His (c.749G>A) in the general population?

SI p.Arg250His (c.749G>A) is ultra-rare (popmax 0.0242%, sas) (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.Arg250His (c.749G>A)?

AlphaMissense predicts likely benign (score 0.1761) — an in-silico prediction, not a clinical call.

SI p.Arg250His

c.749G>A · rs530009542 · VCV903242

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.1761	likely benign
REVEL	0.674	pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	25.9	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 0.0242% South Asian · 22/90,794 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00535% 86/1,607,562 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,127
African / African-American	0.0121%	8,282
Admixed American	0.00671%	14,913
East Asian	0.00449%	22,276
European (non-Finnish)	0.004%	25,015
Remaining individualsnot grpmax-eligible	0.00321%	31,127

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.Arg250His
Coding: c.749G>A
MANE Select: NM_001041
dbSNP: rs530009542
Type: single nucleotide variant
Location: chr3:165065319 (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 250: the 'isomaltase' region; a β-strand

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.Arg250Cys 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
SI c.4927-1G>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-arg250his (accessed [today's date]).

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