SPECC1L

Chr 22AD

sperm antigen with calponin homology and coiled-coil domains 1 like

Also known as: CYTSA, GBBB2, OBLFC1, TBHS, TBHS1

NCBI Gene: 23384ENSG00000100014UniProt: Q69YQ0

This gene encodes a coiled-coil domain containing protein. The encoded protein may play a critical role in actin-cytoskeletal reorganization during facial morphogenesis. Mutations in this gene are a cause of oblique facial clefting-1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A read-through transcript composed of SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and the downstream ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

Primary Disease Associations & Inheritance

?Facial clefting, oblique, 1MIM #600251
AD
Teebi hypertelorism syndrome 1MIM #145420
AD
519
ClinVar variants
59
Pathogenic / LP
0.86
pLI score
2
Active trials
Clinical Summary— SPECC1L
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
59 Pathogenic / Likely Pathogenic· 270 VUS of 519 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.33LOEUF
pLI 0.859
Z-score 5.49
OE 0.20 (0.13–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.60Z-score
OE missense 0.82 (0.76–0.88)
497 obs / 607.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.13–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.76–0.88)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 11 / 54.9Missense obs/exp: 497 / 607.9Syn Z: -0.11

ClinVar Variant Classifications

519 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic17
VUS270
Likely Benign111
Benign39
Conflicting20
42
Pathogenic
17
Likely Pathogenic
270
VUS
111
Likely Benign
39
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
6
36
0
42
Likely Pathogenic
0
6
11
0
17
VUS
10
201
58
1
270
Likely Benign
0
35
22
54
111
Benign
0
11
18
10
39
Conflicting
—20
Total1025914565499

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SPECC1L · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SPECC1L-related facial clefting, oblique

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Facial clefting, oblique, 1

MIM #600251

Molecular basis of disorder known

Autosomal dominant

Teebi hypertelorism syndrome 1

MIM #145420

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Recurrent SPECC1L-NTRK fusions in pediatric sarcoma and brain tumors.
Khuong-Quang DA et al.·Cold Spring Harb Mol Case Stud
2020
Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK -rearranged Myxoid Spindle Cell Neoplasm : A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions.
DeSimone MS et al.·Am J Surg Pathol
2024Cohort
BCL6-SPECC1L: A Novel Fusion Gene in Nasopharyngeal Carcinoma.
Fang SG et al.·Technol Cancer Res Treat
2022
SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.
Migliore C et al.·Genes (Basel)
2022Cohort
Oral Undifferentiated Pleomorphic Sarcoma: A Novel SPECC1L::TERT Gene Fusion and a Comprehensive Literature Review.
Della Mura M et al.·Genes (Basel)
2025Review
Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.
Saadi I et al.·Am J Hum Genet
2011
Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases.
Dickson BC et al.·Mod Pathol
2018Cohort
NGS targeted screening of 100 Scandinavian patients with coronal synostosis.
Topa A et al.·Am J Med Genet A
2020Cohort
Associations of genetic variants contributing to gut microbiota composition in diabetic nephropathy.
Lu X et al.·Front Endocrinol (Lausanne)
2023
Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome.
Bhoj EJ et al.·Am J Med Genet A
2015Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Non-Small Cell Lung CancerMedullary Thyroid CancerColon Cancer

A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

ACTIVE NOT RECRUITING
NCT03157128Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2017-05-02
LOXO-292
Medullary Thyroid CancerInfantile MyofibromatosisInfantile Fibrosarcoma

A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors

ACTIVE NOT RECRUITING
NCT03899792Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2019-06-13
Selpercatinib

External Resources

Links to major genomics databases and tools