Is SIL1 p.Pro3= (c.9C>G) pathogenic?

SIL1 p.Pro3= (c.9C>G) is classified Conflicting classifications of pathogenicity in SIL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00686%, amr); Associated with Marinesco-Sjogren syndrome.

What condition is associated with SIL1 p.Pro3= (c.9C>G)?

SIL1 p.Pro3= (c.9C>G) is associated with Marinesco-Sjogren syndrome (ClinVar).

How common is SIL1 p.Pro3= (c.9C>G) in the general population?

SIL1 p.Pro3= (c.9C>G) is very rare (popmax 0.00686%, amr) (gnomAD).

How is Marinesco-Sjögren syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SIL1 p.Pro3=

c.9C>G · rs369172475 · VCV2069152

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00686%, amr)

Conditions

Marinesco-Sjogren syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -3.3, phastCons 0.001
Overall
CADD	2.163	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00686% Admixed American · 4/58,310 alleles

Filtering AF 0.0023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.002% 32/1,602,370 alleles · very rare exomes 24/1,450,654 · genomes 8/151,716 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00686%	14,577
European (non-Finnish)	0.00238%	41,955

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: SIL1
Protein: p.Pro3=
Coding: c.9C>G
MANE Select: NM_022464
dbSNP: rs369172475
Type: single nucleotide variant
Location: chr5:139127835 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 4 PDB
Residue 3: the 'interaction with hspa5 and localization to the endoplasmic reticulum' region

Full SIL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Marinesco-Sjogren syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Marinesco-Sjögren syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

SIL1 c.1030-9G>A Pathogenic/Likely pathogenic ★★ same condition
SIL1 c.645+2T>C Pathogenic/Likely pathogenic ★★ same condition
SIL1 p.Arg111Ter Pathogenic ★★ same condition
SIL1 p.Gln154Ter Pathogenic ★★ same condition
SIL1 p.Gln438Ter Pathogenic ★★ same condition
SIL1 p.Ala142Pro Uncertain significance ★★ ⚠ same condition
SIL1 p.Ala329Gly Uncertain significance ★★ ⚠ same condition
SIL1 p.Ala329Thr 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/sil1-p-pro3 (accessed [today's date]).

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