Is SIAE p.Cys196Phe (c.587G>T) pathogenic?

SIAE p.Cys196Phe (c.587G>T) is classified Uncertain significance in SIAE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.8893); Ultra-rare (popmax 0.0956%, nfe); Associated with autoimmune disease, susceptibility to, 6.

What condition is associated with SIAE p.Cys196Phe (c.587G>T)?

SIAE p.Cys196Phe (c.587G>T) is associated with autoimmune disease, susceptibility to, 6 (ClinVar).

How common is SIAE p.Cys196Phe (c.587G>T) in the general population?

SIAE p.Cys196Phe (c.587G>T) is ultra-rare (popmax 0.0956%, nfe) (gnomAD).

What do computational predictors say about SIAE p.Cys196Phe (c.587G>T)?

AlphaMissense predicts likely pathogenic (score 0.8893) — an in-silico prediction, not a clinical call.

SIAE p.Cys196Phe

c.587G>T · rs143070599 · VCV1351

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8893 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0956%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune disease, susceptibility to, 6

Computational evidence

Protein change
AlphaMissense	0.8893	likely pathogenic · top 4% in SIAE
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -16.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 37 kb · p 0.0065 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0956% European (non-Finnish) · 1,128/1,180,032 alleles

Filtering AF 0.0909% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.089%

Overall 0.0753% 1,215/1,614,208 alleles · ultra-rare exomes 1,124/1,461,872 · genomes 91/152,336 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0956%	1,046
Remaining individualsnot grpmax-eligible	0.072%	1,389
Admixed American	0.0566%	1,766
African / African-American	0.00933%	10,722
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Cys196Phe
Coding: c.587G>T
MANE Select: NM_170601
dbSNP: rs143070599
Type: single nucleotide variant
Location: chr11:124649754 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.26
Residue 196: a UniProt-annotated variant site (in ais6; defective enzyme secretion and activity)

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

Disease context

autoimmune disease, susceptibility to, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIAE p.Ala385Thr Uncertain significance ★★ ⚠ same condition
SIAE p.Phe404Ser Uncertain significance ★★ ⚠ same condition
SIAE p.Met89Val Benign ★★ same condition
SIAE p.Glu440Lys Uncertain significance ★ ⚠ same condition
SIAE p.Thr312Met Uncertain significance ★ ⚠ same condition
SIAE p.Val431fs Uncertain significance ★ same condition
SIAE p.Arg301His Uncertain significance ★★ ⚠ same type
SIAE p.Arg306Cys 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-cys196phe (accessed [today's date]).

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