Is SIAE p.Ser331Ile (c.992G>T) pathogenic?

SIAE p.Ser331Ile (c.992G>T) is classified Uncertain significance in SIAE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.0871); Very rare (popmax 8.47e-05%, nfe).

How common is SIAE p.Ser331Ile (c.992G>T) in the general population?

SIAE p.Ser331Ile (c.992G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SIAE p.Ser331Ile (c.992G>T)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

SIAE p.Ser331Ile

c.992G>T · VCV3795849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1	GERP -4.2
Regional constraint	o/e 0.89	unconstrained · MANE · 37 kb · p 0.0065 · regional, not allelic
Overall
CADD	1.293	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 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 6.19e-05% 1/1,614,216 alleles · very rare exomes 1/1,461,862 · genomes 0/152,354 · joint denominator

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: SIAE
Protein: p.Ser331Ile
Coding: c.992G>T
MANE Select: NM_170601
Type: single nucleotide variant
Location: chr11:124639842 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.26

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

Similar variants

SIAE p.Ala385Thr Uncertain significance ★★ ⚠ same type
SIAE p.Arg301His Uncertain significance ★★ ⚠ same type
SIAE p.Arg306Cys Uncertain significance ★★ ⚠ same type
SIAE p.Cys196Phe Uncertain significance ★★ ⚠ same type
SIAE p.Cys449Ser Uncertain significance ★★ ⚠ same type
SIAE p.Gln309Arg Uncertain significance ★★ ⚠ same type
SIAE p.Glu399Lys Uncertain significance ★★ ⚠ same type
SIAE p.Glu488Asp Uncertain significance ★★ ⚠ 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/siae-p-ser331ile (accessed [today's date]).

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