Is SI p.Ile616Val (c.1846A>G) pathogenic?

SI p.Ile616Val (c.1846A>G) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1125); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SI p.Ile616Val (c.1846A>G)?

SI p.Ile616Val (c.1846A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Ile616Val (c.1846A>G) in the general population?

SI p.Ile616Val (c.1846A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SI p.Ile616Val (c.1846A>G)?

AlphaMissense predicts likely benign (score 0.1125) — an in-silico prediction, not a clinical call.

SI p.Ile616Val

c.1846A>G · rs2473369858 · VCV2113438

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1125	likely benign
REVEL	0.533	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, 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

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 0.000254% European (non-Finnish) · 3/1,179,554 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,124 alleles · very rare

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.Ile616Val
Coding: c.1846A>G
MANE Select: NM_001041
dbSNP: rs2473369858
Type: single nucleotide variant
Location: chr3:165046882 (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 616: the 'isomaltase' region; an α-helix

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.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
SI p.Arg1078Gln Uncertain significance ★★ same condition
SI p.Arg1078Trp 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-ile616val (accessed [today's date]).

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