Is SI p.Pro173Ala (c.517C>G) pathogenic?

SI p.Pro173Ala (c.517C>G) is classified Benign/Likely benign in SI (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2183); Low-frequency (popmax 4.38%, afr); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Pro173Ala (c.517C>G)?

SI p.Pro173Ala (c.517C>G) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Pro173Ala (c.517C>G) in the general population?

SI p.Pro173Ala (c.517C>G) is low-frequency (popmax 4.38%, 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.Pro173Ala (c.517C>G)?

AlphaMissense predicts likely benign (score 0.2183) — an in-silico prediction, not a clinical call.

SI p.Pro173Ala

c.517C>G · rs146960446 · VCV445929

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2183 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.38%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.2183	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	24.1	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 4.38% African / African-American · 3,277/74,848 alleles

Filtering AF 4.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.2%

Overall 0.235% 3,781/1,610,858 alleles · low-frequency exomes 1,853/1,458,820 · genomes 1,928/152,038 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.38%	23
Admixed American	0.347%	288
Middle Eastern	0.298%	336
Remaining individualsnot grpmax-eligible	0.242%	413
South Asian	0.0121%	8,273
European (non-Finnish)	0.00985%	10,151

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.Pro173Ala
Coding: c.517C>G
MANE Select: NM_001041
dbSNP: rs146960446
Type: single nucleotide variant
Location: chr3:165067458 (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 173: the 'isomaltase' 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.Pro173Leu Uncertain significance ★ ⚠ same residue
SI p.Pro173Ser 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-pro173ala (accessed [today's date]).

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