Is SI p.Val574Ala (c.1721T>C) pathogenic?

SI p.Val574Ala (c.1721T>C) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1978); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SI p.Val574Ala (c.1721T>C)?

SI p.Val574Ala (c.1721T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Val574Ala (c.1721T>C) in the general population?

SI p.Val574Ala (c.1721T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SI p.Val574Ala (c.1721T>C)?

AlphaMissense predicts likely benign (score 0.1978) — an in-silico prediction, not a clinical call.

SI p.Val574Ala

c.1721T>C · VCV4165032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1978 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1978	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 0.65, phastCons 0.99
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	15.42	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SI
Protein: p.Val574Ala
Coding: c.1721T>C
MANE Select: NM_001041
Type: single nucleotide variant
Location: chr3:165047007 (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 574: 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.Val574Leu 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
SI p.Arg1078Gln 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-val574ala (accessed [today's date]).

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