Is SI p.Val194Ile (c.580G>A) pathogenic?

SI p.Val194Ile (c.580G>A) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0716); Very rare (popmax 0.0033%, sas).

How common is SI p.Val194Ile (c.580G>A) in the general population?

SI p.Val194Ile (c.580G>A) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about SI p.Val194Ile (c.580G>A)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

SI p.Val194Ile

c.580G>A · VCV3686291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -5.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -0.48
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	0.906	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 0.0033% South Asian · 3/90,982 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00093% 15/1,612,708 alleles · very rare exomes 15/1,460,612 · genomes 0/152,096 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,327
African / African-American	0.00267%	37,484
Remaining individualsnot grpmax-eligible	0.0016%	62,434
European (non-Finnish)	0.000763%	131,012

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.Val194Ile
Coding: c.580G>A
MANE Select: NM_001041
Type: single nucleotide variant
Location: chr3:165067395 (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 194: the 'isomaltase' region; a β-strand

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

Similar variants

SI p.Val194Phe 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-val194ile (accessed [today's date]).

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