Is SI p.Pro529Arg (c.1586C>G) pathogenic?

SI p.Pro529Arg (c.1586C>G) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.3461); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with SI p.Pro529Arg (c.1586C>G)?

SI p.Pro529Arg (c.1586C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Pro529Arg (c.1586C>G) in the general population?

SI p.Pro529Arg (c.1586C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about SI p.Pro529Arg (c.1586C>G)?

AlphaMissense predicts ambiguous (score 0.3461) — an in-silico prediction, not a clinical call.

SI p.Pro529Arg

c.1586C>G · VCV4630897

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3461	ambiguous
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -12.17	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	26.2	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 0.00134% African / African-American · 1/74,394 alleles

Overall 0.000126% 2/1,588,906 alleles · very rare exomes 2/1,436,836 · genomes 0/152,070 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,394
European (non-Finnish)	8.63e-05%	1,158,549

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.Pro529Arg
Coding: c.1586C>G
MANE Select: NM_001041
Type: single nucleotide variant
Location: chr3:165049802 (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 529: the 'isomaltase' region

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

Similar variants

SI p.Pro529= Likely benign ★★ same residue
SI p.Pro529Leu Uncertain significance ★ ⚠ same residue
SI p.Ala1654Asp Uncertain significance ★★ ⚠ same condition
SI p.Ala429Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala573Val Uncertain significance ★★ ⚠ same condition
SI p.Ala760Val Uncertain significance ★★ ⚠ same condition
SI p.Ala808Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala826Asp Uncertain significance ★★ ⚠ 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-pro529arg (accessed [today's date]).

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