Is SI p.Arg232His (c.695G>A) pathogenic?

SI p.Arg232His (c.695G>A) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0981); Ultra-rare (popmax 0.0144%, sas); Associated with Inborn genetic diseases.

What condition is associated with SI p.Arg232His (c.695G>A)?

SI p.Arg232His (c.695G>A) is associated with Inborn genetic diseases, congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Arg232His (c.695G>A) in the general population?

SI p.Arg232His (c.695G>A) is ultra-rare (popmax 0.0144%, sas) (gnomAD).

What do computational predictors say about SI p.Arg232His (c.695G>A)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

SI p.Arg232His

c.695G>A · rs747345955 · VCV1391599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -3.8, phastCons 0.003
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	16.62	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 0.0144% South Asian · 13/90,552 alleles

Filtering AF 0.00849% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00665%

Overall 0.00403% 64/1,589,150 alleles · ultra-rare exomes 59/1,441,272 · genomes 5/147,878 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0144%	6,966
Remaining individualsnot grpmax-eligible	0.00487%	20,539
European (non-Finnish)	0.00379%	26,391
Admixed American	0.00339%	29,507
African / African-American	0.00272%	36,751

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.Arg232His
Coding: c.695G>A
MANE Select: NM_001041
dbSNP: rs747345955
Type: single nucleotide variant
Location: chr3:165065373 (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 232: the 'isomaltase' region; a β-strand

Full SI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital sucrase-isomaltase deficiency

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-arg232his (accessed [today's date]).

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