Is SMARCA4 p.Ser78Phe (c.233C>T) pathogenic?

SMARCA4 p.Ser78Phe (c.233C>T) is classified Uncertain significance in SMARCA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-20). AlphaMissense: likely benign (0.2461); Absent from gnomAD v4.1; Associated with rhabdoid tumor predisposition syndrome 2.

What condition is associated with SMARCA4 p.Ser78Phe (c.233C>T)?

SMARCA4 p.Ser78Phe (c.233C>T) is associated with rhabdoid tumor predisposition syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is SMARCA4 p.Ser78Phe (c.233C>T) in the general population?

SMARCA4 p.Ser78Phe (c.233C>T) is absent from gnomAD v4.1 (gnomAD).

How is Rhabdoid tumor predisposition syndrome inherited?

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

What do computational predictors say about SMARCA4 p.Ser78Phe (c.233C>T)?

AlphaMissense predicts likely benign (score 0.2461) — an in-silico prediction, not a clinical call.

SMARCA4 p.Ser78Phe

c.233C>T · rs1555751949 · VCV1442002

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2461 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

rhabdoid tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2461	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,200 bp · p 0.0027 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMARCA4
Protein: p.Ser78Phe
Coding: c.233C>T
MANE Select: NM_003072
dbSNP: rs1555751949
Type: single nucleotide variant
Location: chr19:10985283 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 78: the 'necessary for interaction with ss18l1/crest' region; the 'disordered' region

Full SMARCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

rhabdoid tumor predisposition syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Rhabdoid tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

SMARCA4 p.Ser78Pro Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Ser78Tyr Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Ser78= Likely benign ★★ same residue
SMARCA4 p.Ser78Ala Uncertain significance ★ ⚠ same residue
SMARCA4 c.1943+1G>A Likely pathogenic ★★ same condition
SMARCA4 c.2274+1G>T Likely pathogenic ★★ same condition
SMARCA4 c.2438+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMARCA4 c.3216-1G>C Likely 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/smarca4-p-ser78phe (accessed [today's date]).

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