Is SI p.Trp552Cys (c.1656G>C) pathogenic?

SI p.Trp552Cys (c.1656G>C) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.869); Very rare (popmax 0.00224%, eas); Associated with Inborn genetic diseases.

What condition is associated with SI p.Trp552Cys (c.1656G>C)?

SI p.Trp552Cys (c.1656G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Trp552Cys (c.1656G>C) in the general population?

SI p.Trp552Cys (c.1656G>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about SI p.Trp552Cys (c.1656G>C)?

AlphaMissense predicts likely pathogenic (score 0.869) — an in-silico prediction, not a clinical call.

SI p.Trp552Cys

c.1656G>C · rs1415993217 · VCV3162026

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.869	likely pathogenic
REVEL	0.732	pathogenic-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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	27.8	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 0.00224% East Asian · 1/44,724 alleles

Overall 0.00132% 2/152,082 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,724
African / African-American	0.00134%	74,862

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.Trp552Cys
Coding: c.1656G>C
MANE Select: NM_001041
dbSNP: rs1415993217
Type: single nucleotide variant
Location: chr3:165049186 (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 552: 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.Trp552Arg Uncertain significance ★★ ⚠ same residue
SI p.Trp552Ter Likely pathogenic ★ 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-trp552cys (accessed [today's date]).

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