Is SMARCE1 p.Pro399Leu (c.1196C>T) pathogenic?

SMARCE1 p.Pro399Leu (c.1196C>T) is classified Conflicting classifications of pathogenicity in SMARCE1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0665); Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCE1 p.Pro399Leu (c.1196C>T)?

SMARCE1 p.Pro399Leu (c.1196C>T) is associated with hereditary neoplastic syndrome, familial meningioma (ClinVar).

How common is SMARCE1 p.Pro399Leu (c.1196C>T) in the general population?

SMARCE1 p.Pro399Leu (c.1196C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SMARCE1 p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

SMARCE1 p.Pro399Leu

c.1196C>T · rs1397941319 · VCV1361984

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,097 bp · p 0.26 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

Overall 0.000205% 3/1,461,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
East Asian	0.00223%	44,884
European (non-Finnish)	8.48e-05%	1,179,728

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.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_003079
dbSNP: rs1397941319
Type: single nucleotide variant
Location: chr17:40628825 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.72 · 8 PDB
Residue 399: 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.Pro399Ala Conflicting classifications of pathogenicity ★ ⚠ 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
SMARCE1 p.Glu110Ter Pathogenic ★★ same condition
SMARCE1 p.Glu165Ter 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-pro399leu (accessed [today's date]).

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