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: Q69YQ0OMIM: 614140

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]

OMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 0.332 OMIM phenotypes
Clinical Summary— SPECC1L
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Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.
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ClinVar Variants
14 unique Pathogenic / Likely Pathogenic· 238 VUS of 421 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
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?
1.60Z-score
OE missense 0.82 (0.76–0.88)
497 obs / 607.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.20 (0.13–0.33)
0≤0.351.4
Missense OE?0.82 (0.76–0.88)
0≤0.61.4
Synonymous OE?1.01
0≤1.21.6
LoF obs/exp: 11 / 54.9Missense obs/exp: 497 / 607.9Syn Z: -0.11
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongSPECC1L-related Teebi hypertelorism syndromeOTHERAD
limitedSPECC1L-related facial clefting, obliqueOTHERAD

This gene — mechanism propensity

DN
0.5181th %ile
GOF
0.5464th %ile
LOF
0.62top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.33
GOF1 literature citation · 100% of P/LP are missense

Literature Evidence

GOFIn-frame deletion of SPECC1L microtubule association domain results in gain-of-function phenotypes affecting embryonic tissue movement and fusion events.1
LOFWe confirmed SPECC1L haploinsufficiency at the RNA level in DGAP177 lymphoblastoid cells by using conventional and quantitative real-time RT-PCR (Figures 1C and 1D).2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 34302166 ↗
  2. 2.PMID 21703590 ↗

ClinVar Variant Classifications

421 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic6
VUS238
Likely Benign111
Benign38
Conflicting20
8
Pathogenic
6
Likely Pathogenic
238
VUS
111
Likely Benign
38
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
8
0
0
8
Likely Pathogenic
0
6
0
0
6
VUS
20
207
10
1
238
Likely Benign
0
35
21
55
111
Benign
0
11
17
10
38
Conflicting
—20
Total202674866421

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

View in ClinVar →

51 pathogenic / likely-pathogenic (of 104) ClinVar copy-number / structural variants overlap SPECC1L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

SPECC1L · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients