Is SI p.Arg588His (c.1763G>A) pathogenic?

SI p.Arg588His (c.1763G>A) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely pathogenic (0.8816); Ultra-rare (popmax 0.0144%, sas).

How common is SI p.Arg588His (c.1763G>A) in the general population?

SI p.Arg588His (c.1763G>A) is ultra-rare (popmax 0.0144%, sas) (gnomAD).

What do computational predictors say about SI p.Arg588His (c.1763G>A)?

AlphaMissense predicts likely pathogenic (score 0.8816) — an in-silico prediction, not a clinical call.

SI p.Arg588His

c.1763G>A · VCV3625795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8816	likely pathogenic
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -13.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 · 13/90,512 alleles

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

Overall 0.0018% 29/1,611,418 alleles · ultra-rare exomes 27/1,459,388 · genomes 2/152,030 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0144%	6,962
Finnishnot grpmax-eligible	0.00626%	15,972
Admixed American	0.00167%	59,816
Remaining individualsnot grpmax-eligible	0.0016%	62,360
European (non-Finnish)	0.000848%	117,882

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.Arg588His
Coding: c.1763G>A
MANE Select: NM_001041
Type: single nucleotide variant
Location: chr3:165046965 (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 588: the 'isomaltase' region; a β-strand

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

Similar variants

SI p.Arg588Cys Uncertain significance ★★ ⚠ same residue
SI c.2426+1G>A Likely pathogenic ★★ same type
SI c.2737-2A>G Likely pathogenic ★★ same type
SI c.2893-1G>A Likely pathogenic ★★ same type
SI c.3099+1G>C Likely pathogenic ★★ same type
SI c.3521-1G>T Likely pathogenic ★★ same type
SI c.373+1G>A Likely pathogenic ★★ same type
SI c.4575+2T>C Likely pathogenic ★★ same type

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-arg588his (accessed [today's date]).

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