Is SMARCAL1 p.Ser774Ter (c.2321C>A) pathogenic?

SMARCAL1 p.Ser774Ter (c.2321C>A) is classified Pathogenic in SMARCAL1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Very rare (popmax 0.000339%, nfe); Associated with Schimke immuno-osseous dysplasia.

What condition is associated with SMARCAL1 p.Ser774Ter (c.2321C>A)?

SMARCAL1 p.Ser774Ter (c.2321C>A) is associated with Schimke immuno-osseous dysplasia (ClinVar).

How common is SMARCAL1 p.Ser774Ter (c.2321C>A) in the general population?

SMARCAL1 p.Ser774Ter (c.2321C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Schimke immuno-osseous dysplasia inherited?

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

SMARCAL1 p.Ser774Ter

c.2321C>A · rs149425324 · VCV463148

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Schimke immuno-osseous dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.62, phastCons 0.52
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,886 alleles · very rare

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: SMARCAL1
Protein: p.Ser774Ter
Coding: c.2321C>A
MANE Select: NM_014140
dbSNP: rs149425324
Type: single nucleotide variant
Location: chr2:216475345 (GRCh38)
Gene constraint: LOEUF 0.795 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.51 · 1 PDB
Residue 774: the helicase c-terminal domain

Full SMARCAL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Schimke immuno-osseous dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Schimke immuno-osseous dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

SMARCAL1 p.Ser774Leu Uncertain significance ★★ ⚠ same residue
SMARCAL1 p.Ser774= Conflicting classifications of pathogenicity ★ same residue
SMARCAL1 p.Ser774Pro Uncertain significance ★ same residue
SMARCAL1 p.Ser774Trp Uncertain significance ★ ⚠ same residue
SMARCAL1 c.1334+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMARCAL1 c.1485+1G>A Likely pathogenic ★★ same condition
SMARCAL1 c.1710+2T>C Likely pathogenic ★★ same condition
SMARCAL1 c.2427+1G>A 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/smarcal1-p-ser774ter (accessed [today's date]).

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