Is SMARCE1 p.Pro45= (c.135G>A) pathogenic?

SMARCE1 p.Pro45= (c.135G>A) is classified Likely benign in SMARCE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-22). Ultra-rare (popmax 0.0176%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCE1 p.Pro45= (c.135G>A)?

SMARCE1 p.Pro45= (c.135G>A) is associated with hereditary neoplastic syndrome, familial meningioma (ClinVar).

How common is SMARCE1 p.Pro45= (c.135G>A) in the general population?

SMARCE1 p.Pro45= (c.135G>A) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

SMARCE1 p.Pro45=

c.135G>A · rs148373393 · VCV239490

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.3, phastCons 1
Overall
CADD	14.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% South Asian · 16/90,968 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00899%

Overall 0.00373% 60/1,609,562 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,686
African / African-American	0.016%	6,234
European (non-Finnish)	0.00247%	40,567
East Asian	0.00223%	44,878
Admixed American	0.00167%	59,996
Finnishnot grpmax-eligible	0.00156%	64,016

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: SMARCE1
Protein: p.Pro45=
Coding: c.135G>A
MANE Select: NM_003079
dbSNP: rs148373393
Type: single nucleotide variant
Location: chr17:40642476 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.72 · 8 PDB
Residue 45: the 'disordered' region

Full SMARCE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial meningioma

Similar variants

SMARCE1 p.Pro45Leu Uncertain significance ★★ ⚠ same residue
SMARCE1 p.Pro45Ser Uncertain significance ★★ ⚠ same residue
SMARCE1 p.Pro45Ala Uncertain significance ★ ⚠ same residue
SMARCE1 p.Arg105Gln Pathogenic/Likely pathogenic ★★ same condition
SMARCE1 p.Arg158Ter Pathogenic ★★ same condition
SMARCE1 p.Arg239Ter Pathogenic ★★ same condition
SMARCE1 p.Arg251Ter Pathogenic/Likely pathogenic ★★ same condition
SMARCE1 p.Gln225Ter Pathogenic ★★ 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/smarce1-p-pro45 (accessed [today's date]).

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